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chapter 2 Structure and Functions of Cells of the Nervous System
Outline
· ■ Cells of the Nervous System
· ■ Communication Within a Neuron
Neural Communication: An Overview
Measuring Electrical Potentials of Axons
The Membrane Potential: Balance of Two Forces
Conduction of the Action Potential
· ■ Communication Between Neurons
Termination of Postsynaptic Potentials
Effects of Postsynaptic Potentials: Neural Integration
Nonsynaptic Chemical Communication
Kathryn D. was getting desperate. All her life she had been healthy and active, eating wisely and keeping fit with sports and regular exercise. She went to her health club almost every day for a session of low-impact aerobics followed by a swim. But several months ago she began having trouble keeping up with her usual schedule. At first, she found herself getting tired toward the end of her aerobics class. Her arms, particularly, seemed to get heavy. Then when she entered the pool and started swimming, she found that it was hard to lift her arms over her head; she abandoned the crawl and the backstroke and did the sidestroke and breaststroke instead. She did not have any flulike symptoms, so she told herself that she needed more sleep and perhaps she should eat a little more.
Over the next few weeks, however, things only got worse. Aerobics classes were becoming an ordeal. Her instructor became concerned and suggested that Kathryn see her doctor. She did so, but he could find nothing wrong with her. She was not anemic, showed no signs of an infection, and seemed to be well nourished. He asked how things were going at work.
“Well, lately I’ve been under some pressure,” she said. “The head of my department quit a few weeks ago, and I’ve taken over his job temporarily. I think I have a chance of getting the job permanently, but I feel as if my bosses are watching me to see whether I’m good enough for the job.” Kathryn and her physician agreed that increased stress could be the cause of her problem. “I’d prefer not to give you any medication at this time,” he said, “but if you don’t feel better soon we’ll have a closer look at you.”
She did feel better for a while, but then all of a sudden her symptoms got worse. She quit going to the health club and found that she even had difficulty finishing a day’s work. She was certain that people were noticing that she was no longer her lively self, and she was afraid that her chances for the promotion were slipping away. One afternoon she tried to look up at the clock on the wall and realized that she could hardly see—her eyelids were drooping, and her head felt as if it weighed a hundred pounds. Just then, one of her supervisors came over to her desk, sat down, and asked her to fill him in on the progress she had been making on a new project. As she talked, she found herself getting weaker and weaker. Her jaw was getting tired, even her tongue was getting tired, and her voice was getting weaker. With a sudden feeling of fright she realized that the act of breathing seemed to take a lot of effort. She managed to finish the interview, but immediately afterward she packed up her briefcase and left for home, saying that she had a bad headache.
She telephoned her physician, who immediately arranged for her to go to the hospital to be seen by Dr. T., a neurologist. Dr. T. listened to a description of Kathryn’s symptoms and examined her briefly. She said to Kathryn, “I think I know what may be causing your symptoms. I’d like to give you an injection and watch your reaction.” She gave some orders to the nurse, who left the room and came back with a syringe. Dr. T. took it, swabbed Kathryn’s arm, and injected the drug. She started questioning Kathryn about her job. Kathryn answered slowly, her voice almost a whisper. As the questions continued, she realized that it was getting easier and easier to talk. She straightened her back and took a deep breath. Yes, she was sure. Her strength was returning! She stood up and raised her arms above her head. “Look,” she said, her excitement growing. “I can do this again. I’ve got my strength back! What was that you gave me? Am I cured?”
(For an answer to her question, see p. 59 .)
All we can do—perceive, think, learn, remember, act—is made possible by the integrated activity of the cells of the nervous system. This chapter describes the structure and functions of these cells. Information, in the form of light, sound waves, odors, tastes, or contact with objects, is gathered from the environment by specialized cells called sensory neurons . Movements are accomplished by the contraction of muscles, which are controlled by motor neurons . (The term motor is used here in its original sense to refer to movement, not to a mechanical engine.) And in between sensory neurons and motor neurons come the interneurons —neurons that lie entirely within the central nervous system. Local interneurons form circuits with nearby neurons and analyze small pieces of information. Relay interneurons connect circuits of local interneurons in one region of the brain with those in other regions. Through these connections, circuits of neurons throughout the brain perform functions essential to tasks such as perceiving, learning, remembering, deciding, and controlling complex behaviors. How many neurons are there in the human nervous system? The most common estimate is around 100 billion, but no one has counted them yet.
To understand how the nervous system controls behavior, we must first understand its parts—the cells that compose it. Because this chapter deals with cells, you need not be familiar with the structure of the nervous system, which is presented in Chapter 3 . However, you need to know that the nervous system consists of two basic divisions: the central nervous system and the peripheral nervous system. The central nervous system (CNS) consists of the parts that are encased by the bones of the skull and spinal column: the brain and the spinal cord. The peripheral nervous system (PNS) is found outside these bones and consists of the nerves and most of the sensory organs.
Cells of the Nervous System
The first part of this chapter is devoted to a description of the most important cells of the nervous system—neurons and their supporting cells—and to the blood–brain barrier, which provides neurons in the central nervous system with chemical isolation from the rest of the body.
Neurons
BASIC STRUCTURE
The neuron (nerve cell) is the information-processing and information-transmitting element of the nervous system. Neurons come in many shapes and varieties, according to the specialized jobs they perform. Most neurons have, in one form or another, the following four structures or regions: (1) cell body, or soma; (2) dendrites; (3) axon; and (4) terminal buttons. To see an interactive animation of the information presented in the following section,
Soma.
The soma (cell body) contains the nucleus and much of the machinery that provides for the life processes of the cell. (See Figure 2.1 . ) Its shape varies considerably in different kinds of neurons.
Dendrites.
FIGURE 2.1 The Principal Parts of a Multipolar Neuron
Dendron is the Greek word for tree, and the dendrites of the neuron look very much like trees. (Look again at Figure 2.1 .) Neurons “converse” with one another, and dendrites serve as important recipients of these messages. The messages that pass from neuron to neuron are transmitted across the synapse , a junction between the terminal buttons (described later) of the sending cell and a portion of the somatic or dendritic membrane of the receiving cell. (The word synapse derives from the Greek sunaptein, “to join together.”) Communication at a synapse proceeds in one direction: from the terminal button to the membrane of the other cell. (Like many general rules, this one has some exceptions. As we will see in Chapter 4 , some synapses pass information in both directions.)
Axon.
The axon is a long, slender tube, often covered by a myelin sheath. (The myelin sheath is described later.) The axon carries information from the cell body to the terminal buttons. (Look again at Figure 2.1 .) The basic message it carries is called an action potential. This function is an important one and will be described in more detail later in the chapter. For now, it suffices to say that an action potential is a brief electrical/chemical event that starts at the end of the axon next to the cell body and travels toward the terminal buttons. The action potential is like a brief pulse; in any given axon the action potential is always of the same size and duration. When it reaches a point where the axon branches, it splits but does not diminish in size. Each branch receives a full-strength action potential.
Like dendrites, axons and their branches come in different shapes. In fact, the three principal types of neurons are classified according to the way in which their axons and dendrites leave the soma. The neuron depicted in Figure 2.1 is the most common type found in the central nervous system; it is a multipolar neuron . In this type of neuron the somatic membrane gives rise to one axon but to the trunks of many dendritic trees. Bipolar neurons give rise to one axon and one dendritic tree, at opposite ends of the soma. (See Figure 2.2a . ) Bipolar neurons are usually sensory; that is, their dendrites detect events occurring in the environment and communicate information about these events to the central nervous system.
The third type of nerve cell is the unipolar neuron . It has only one stalk, which leaves the soma and divides into two branches a short distance away. (See Figure 2.2b . )
Unipolar neurons, like bipolar neurons, transmit sensory information from the environment to the CNS. The arborizations (treelike branches) outside the CNS are dendrites; the arborizations within the CNS end in terminal buttons. The dendrites of most unipolar neurons detect touch, temperature changes, and other sensory events that affect the skin. Other unipolar neurons detect events in our joints, muscles, and internal organs.
The central nervous system communicates with the rest of the body through nerves attached to the brain and to the spinal cord. Nerves are bundles of many thousands of individual fibers, all wrapped in a tough, protective membrane. Under a microscope, nerves look something like telephone cables, with their bundles of wires. (See Figure 2.3 . ) Like the individual wires in a telephone cable, nerve fibers transmit messages through the nerve, from a sense organ to the brain or from the brain to a muscle or gland.
FIGURE 2.2 Neurons
Pictured here are (a) a bipolar neuron, primarily found in sensory systems (for example, vision and audition), and (b) a unipolar neuron, found in the somatosensory system (touch, pain, and the like).
Terminal Buttons.
Most axons divide and branch many times. At the ends of the twigs are found little knobs called terminal buttons . (Some neuroscientists prefer the original French word bouton, and others simply refer to them as terminals.) Terminal buttons have a very special function: When an action potential traveling down the axon reaches them, they secrete a chemical called a neurotransmitter . This chemical (there are many different ones in the CNS) either excites or inhibits the receiving cell and thus helps to determine whether an action potential occurs in its axon. Details of this process will be described later in this chapter.
An individual neuron receives information from the terminal buttons of axons of other neurons—and the terminal buttons of its axons form synapses with other neurons. A neuron may receive information from dozens or even hundreds of other neurons, each of which can form a large number of synaptic connections with it. Figure 2.4 illustrates the nature of these connections. As you can see, terminal buttons can form synapses on the membrane of the dendrites or the soma. (See Figure 2.4 . )
INTERNAL STRUCTURE
FIGURE 2.3 Nerves
A nerve consists of a sheath of tissue that encases a bundle of individual nerve fibers (also known as axons). BV = blood vessel; A = individual axons.
(From Tissues and Organs: A Text-Atlas of Scanning Electron Microscopy, by Richard G. Kessel and Randy H. Kardon. Copyright © 1979 by W. H. Freeman and Co. Reprinted by permission of Barbara Kessel and Randy Kardon.)
Figure 2.5 illustrates the internal structure of a typical multipolar neuron. (See Figure 2.5 . ) The membrane defines the boundary of the cell. It consists of a double layer of lipid (fatlike) molecules. Embedded in the membrane are a variety of protein molecules that have special functions. Some proteins detect substances outside the cell (such as hormones) and pass information about the presence of these substances to the interior of the cell. Other proteins control access to the interior of the cell, permitting some substances to enter but barring others. Still other proteins act as transporters, actively carrying certain molecules into or out of the cell. Because the proteins that are found in the membrane of the neuron are especially important in the transmission of information, their characteristics will be discussed in more detail later in this chapter.
FIGURE 2.4 An Overview of the Synaptic Connections Between Neurons
The arrows represent the directions of the flow of information.
FIGURE 2.5 The Principal Internal Structures of a Multipolar Neuron
The nucleus (“nut”) of the cell is round or oval and is enclosed by the nuclear membrane. The nucleolus and the chromosomes reside here. The nucleolus is responsible for the production of ribosomes , small structures that are involved in protein synthesis. The chromosomes , which consist of long strands of deoxyribonucleic acid (DNA) , contain the organism’s genetic information. When they are active, portions of the chromosomes ( genes ) cause production of another complex molecule, messenger ribonucleic acid (mRNA) , which receives a copy of the information stored at that location. The mRNA leaves the nuclear membrane and attaches to ribosomes, where it causes the production of a particular protein. (See Figure 2.6 . )
Proteins are important in cell functions. As well as providing structure, proteins serve as enzymes , which direct the chemical processes of a cell by controlling chemical reactions. Enzymes are special protein molecules that act as catalysts; that is, they cause a chemical reaction to take place without becoming a part of the final product themselves. Because cells contain the ingredients needed to synthesize an enormous variety of compounds, the ones that cells actually do produce depend primarily on the particular enzymes that are present. Furthermore, there are enzymes that break molecules apart as well as enzymes that put them together; the enzymes that are present in a particular region of a cell thus determine which molecules remain intact. For example,
In this reversible reaction the relative concentrations of enzymes X and Y determine whether the complex substance AB or its constituents, A and B, will predominate. Enzyme X makes A and B join together; enzyme Y splits AB apart. (Energy may also be required to make the reactions proceed.)
FIGURE 2.6 Protein Synthesis
When a gene is active, a copy of the information is made onto a molecule of messenger RNA. The mRNA leaves the nucleus and attaches to a ribosome, where the protein is produced.
As you undoubtedly know, the sequence of the human genome—along with that of several other plants and animals—has been determined. (The genome is the sequence of nucleotide bases on the chromosomes that provide the information needed to synthesize all the proteins that can be produced by a particular organism.) Biologists were surprised to learn that the number of genes was not correlated with the complexity of the organism (Mattick, 2004 ). For example, Caenorhabditis elegans, a simple worm that consists of about 1000 cells, has 19,000 genes, whereas humans have around 25,000 genes. The research also revealed that the genomes of most vertebrates contained much “junk” DNA, which did not contain information needed to produce proteins. For example, only about 1.5 percent of the human genome encodes for proteins. At first, molecular geneticists assumed that “junk” DNA was a leftover from our evolutionary history and that only the sequences of DNA that encoded for proteins were useful. However, further research found that the amount of non-protein-coding DNA did correlate well with the complexity of an organism and that many of these sequences have been conserved for millions of years. In other words, it started looking as though “junk” DNA was not junk after all. (See Figure 2.7 . )
FIGURE 2.7 Non-coding DNA
This figure shows the percentage of DNA that does not code for proteins in various categories of living organisms.
(Adapted from Mattick, J. S. Scientific American, 2004, 291, 60–67.)
A study by Woolfe et al. ( 2005 ) illustrates the longevity of most non-coding DNA. The researchers compared the genomes of the human and the pufferfish. The common ancestor of these two species lived many millions of years ago, which means that if non-coding DNA is really just useless, leftover junk, then random mutations should have produced many changes in their sequences. However, Woolfe and his colleagues found 1400 highly conserved non-coding sequences, many of which were over 90 percent identical in humans and pufferfish. In addition, they found that these conserved sequences were located near genes that control development, which is unlikely to be a coincidence. In fact, we will see in Chapter 3 that mutations in non-coding regions of the human genome appear to be responsible for the increased size and complexity of the human brain.
What do these non-coding sequences of DNA do? Although their sequences can be transcribed into RNA, this RNA does not result in the production of protein. Instead, non-coding RNA (ncRNA) appears to have functions of it own. For example, when most genes become active, segments of DNA are transcribed into molecules of messenger RNA, and then other molecules cut the mRNA into pieces, discard some parts, and splice the remaining pieces together. The resulting chunk of mRNA then contains the information required for the construction of the protein. The cutting and splicing are accomplished by molecular complexes called spliceosomes, and one of the constituents of spliceosomes is non-coding RNA. Molecules of ncRNA also attach to—and modify—proteins that regulate gene expression (Szymanski et al., 2003 ; Storz, Altuvia, and Wassarman, 2005 ; Satterlee et al., 2007 ). Thus, the human genome, more broadly defined to include non-coding RNA, is much larger than biologists previously believed.
The bulk of the cell consists of cytoplasm. Cytoplasm is complex and varies considerably across types of cells, but it can most easily be characterized as a jellylike, semiliquid substance that fills the space outlined by the membrane. It contains small, specialized structures, just as the body contains specialized organs. The generic term for these structures is organelle, “little organ.” The most important organelles are described next.
Mitochondria (singular: mitochondrion) are shaped like oval beads and are formed of a double membrane. The inner membrane is wrinkled, and the wrinkles make up a set of shelves (cristae) that fill the inside of the bead. Mitochondria perform a vital role in the economy of the cell; many of the biochemical steps that are involved in the extraction of energy from the breakdown of nutrients take place on the cristae, controlled by enzymes located there. Most cell biologists believe that many eons ago, mitochondria were free-living organisms that came to “infect” larger cells. Because the mitochondria could extract energy more efficiently than the cells they infected, the mitochondria became useful to the cells and eventually became a permanent part of them. Cells provide mitochondria with nutrients, and mitochondria provide cells with a special molecule— adenosine triphosphate (ATP) —that cells use as their immediate source of energy. Mitochondria contain their own DNA and reproduce independently of the cells in which they reside.
Endoplasmic reticulum , which serves as a storage reservoir and as a channel for transporting chemicals through the cytoplasm, appears in two forms: rough and smooth. Both types consist of parallel layers of membrane, arranged in pairs, of the sort that encloses the cell. Rough endoplasmic reticulum contains ribosomes. The protein produced by the ribosomes that are attached to the rough endoplasmic reticulum is destined to be transported out of the cell or used in the membrane. Unattached ribosomes are also distributed around the cytoplasm; the unattached variety appears to produce protein for use within the neuron. Smooth endoplasmic reticulum provides channels for the segregation of molecules involved in various cellular processes. Lipid (fatlike) molecules are also produced here.
The Golgi apparatus is a special form of smooth endoplasmic reticulum. Some complex molecules, made up of simpler individual molecules, are assembled here. The Golgi apparatus also serves as a wrapping or packaging agent. For example, secretory cells (such as those that release hormones) wrap their product in a membrane produced by the Golgi apparatus. When the cell secretes its products, it uses a process called exocytosis (exo, “outside”; cyto, “cell”; -osis, “process”). Briefly stated, the container migrates to the inside of the outer membrane of the cell, fuses with it, and bursts, spilling its contents into the fluid surrounding the cell. As we will see, neurons communicate with one another by secreting chemicals by this means. Therefore, I will describe the process of exocytosis in more detail later in this chapter. The Golgi apparatus also produces lysosomes , small sacs that contain enzymes that break down substances no longer needed by the cell. These products are then recycled or excreted from the cell.
FIGURE 2.8 Fast Axoplasmic Transport
This figure shows how kinesin molecules (a) “walk” down a microtubule, carrying their cargo from the soma to the terminal buttons. Another protein, dynein, carries substances from the terminal buttons to the soma. (b) A photomicrograph of a mouse axon, showing an organelle being transported along a microtubule. The arrow points to what appears to be a kinesin molecule.
(From Hirokawa, N. Science, 1998, 279, 519–526. Copyright © 1998 American Association for the Advancement of Science. Reprinted with permission.)
If a neuron grown in a tissue culture is exposed to a detergent, the lipid membrane and much of the interior of the cell dissolve away, leaving a matrix of insoluble strands of protein. This matrix, called the cytoskeleton , gives the neuron its shape. The cytoskeleton is made of three kinds of protein strands, linked to each other and forming a cohesive mass. The thickest of these strands, microtubules , are bundles of thirteen protein filaments arranged around a hollow core.
Axons can be extremely long relative to their diameter and the size of the soma. For example, the longest axon in a human stretches from the foot to a region located in the base of the brain. Because terminal buttons need some items that can be produced only in the soma, there must be a system that can transport these items rapidly and efficiently through the axoplasm (that is, the cytoplasm of the axon). This system is referred to as axoplasmic transport , an active process by which substances are propelled along microtubules that run the length of the axon. Movement from the soma to the terminal buttons is called anterograde axoplasmic transport. (Antero- means “toward the front.”) This form of transport is accomplished by molecules of a protein called kinesin. In the cell body, kinesin molecules, which resemble a pair of legs and feet, attach to the item being transported down the axon. The kinesin molecule then walks down a microtubule, carrying the cargo to its destination (Yildiz et al., 2004 ). Energy is supplied by ATP molecules produced by the mitochondria. (See Figure 2.8 . ) Another protein, dynein, carries substances from the terminal buttons to the soma, a process known as retrograde axoplasmic transport. Anterograde axoplasmic transport is remarkably fast: up to 500 mm per day. Retrograde axoplasmic transport is about half as fast as anterograde transport.
Supporting Cells
Neurons constitute only about half the volume of the CNS. The rest consists of a variety of supporting cells. Because neurons have a very high rate of metabolism but have no means of storing nutrients, they must constantly be supplied with nutrients and oxygen or they will quickly die. Thus, the role played by the cells that support and protect neurons is very important to our existence.
GLIA
The most important supporting cells of the central nervous system are the neuroglia, or “nerve glue.” Glia (also called glial cells) do indeed glue the CNS together, but they do much more than that. Neurons lead a very sheltered existence; they are buffered physically and chemically from the rest of the body by the glial cells. Glial cells surround neurons and hold them in place, controlling their supply of nutrients and some of the chemicals they need to exchange messages with other neurons; they insulate neurons from one another so that neural messages do not get scrambled; and they even act as housekeepers, destroying and removing the carcasses of neurons that are killed by disease or injury.
There are several types of glial cells, each of which plays a special role in the CNS. The three most important types are astrocytes, oligodendrocytes, and microglia. Astrocyte means “star cell,” and this name accurately describes the shape of these cells. Astrocytes provide physical support to neurons and clean up debris within the brain. They produce some chemicals that neurons need to fulfill their functions. They help to control the chemical composition of the fluid surrounding neurons by actively taking up or releasing substances whose concentrations must be kept within critical levels. Finally, astrocytes are involved in providing nourishment to neurons.
Some of the astrocyte’s processes (the arms of the star) are wrapped around blood vessels; other processes are wrapped around parts of neurons, so the somatic and dendritic membranes of neurons are largely surrounded by astrocytes. This arrangement suggested to the Italian histologist Camillo Golgi (1844–1926) that astrocytes supplied neurons with nutrients from the capillaries and disposed of their waste products (Golgi, 1903 ). He thought that nutrients passed from capillaries to the cytoplasm of the astrocytes and then through the cytoplasm to the neurons.
Recent evidence suggests that Golgi was right: Although neurons receive some glucose directly from capillaries, they receive most of their nutrients from astrocytes. Astrocytes receive glucose from capillaries and break it down to lactate, the chemical produced during the first step of glucose metabolism. They then release lactate into the extracellular fluid that surrounds neurons, and neurons take up the lactate, transport it to their mitochondria, and use it for energy (Tsacopoulos and Magistretti, 1996 ; Brown, Tekkök, and Ransom, 2003; Pellerin et al., 2007 ). Apparently, this process provides neurons with a fuel that they can metabolize even more rapidly than glucose. In addition, astrocytes store a small amount of a carbohydrate called glycogen that can be broken down to glucose and then to lactate when the metabolic rate of neurons in their vicinity is especially high. (See Figure 2.9 . )
Besides transporting chemicals to neurons, astrocytes serve as the matrix that holds neurons in place—the “nerve glue,” so to speak. These cells also surround and isolate synapses, limiting the dispersion of neurotransmitters that are released by the terminal buttons.
When cells in the central nervous system die, certain kinds of astrocytes take up the task of cleaning away the debris. These cells are able to travel around the CNS; they extend and retract their processes (pseudopodia, or “false feet”) and glide about the way amoebas do. When these astrocytes contact a piece of debris from a dead neuron, they push themselves against it, finally engulfing and digesting it. We call this process phagocytosis (phagein, “to eat”; kutos, “cell”). If there is a considerable amount of injured tissue to be cleaned up, astrocytes will divide and produce enough new cells to do the task. Once the dead tissue has been broken down, a framework of astrocytes will be left to fill in the vacant area, and a specialized kind of astrocyte will form scar tissue, walling off the area.
FIGURE 2.9 Structure and Location of Astrocytes
The processes of astrocytes surround capillaries and neurons of the central nervous system.
The principal function of oligodendrocytes is to provide support to axons and to produce the myelin sheath , which insulates most axons from one another. (Very small axons are not myelinated and lack this sheath.) Myelin, 80 percent lipid and 20 percent protein, is produced by the oligodendrocytes in the form of a tube surrounding the axon. This tube does not form a continuous sheath; rather, it consists of a series of segments, each approximately 1 mm long, with a small (1–2 μm) portion of uncoated axon between the segments. (A micrometer, abbreviated μm, is one-millionth of a meter, or one-thousandth of a millimeter.) The bare portion of axon is called a node of Ranvier , after the person who discovered it. The myelinated axon, then, resembles a string of elongated beads. (Actually, the beads are very much elongated—their length is approximately 80 times their width.)
FIGURE 2.10 Oligodendrocyte
An oligodendrocyte forms the myelin that surrounds many axons in the central nervous system. Each cell forms one segment of myelin for several adjacent axons.
A given oligodendrocyte produces up to fifty segments of myelin. During the development of the CNS, oligodendrocytes form processes shaped something like canoe paddles. Each of these paddle-shaped processes then wraps itself many times around a segment of an axon and, while doing so, produces layers of myelin. Each paddle thus becomes a segment of an axon’s myelin sheath. (See Figures 2.10 and 2.11a . )
FIGURE 2.11 Formation of Myelin
During development a process of an oligodendrocyte or an entire Schwann cell tightly wraps itself many times around an individual axon and forms one segment of the myelin sheath. (a) Oligodendrocyte. (b) Schwann cell.
Dr. C., a retired neurologist, had been afflicted with multiple sclerosis for more than two decades when she died of a heart attack. One evening, twenty-three years previously, she and her husband had had dinner at their favorite restaurant. As they were leaving, she stumbled and almost fell. Her husband joked, “Hey, honey, you shouldn’t have had that last glass of wine.” She smiled at his attempt at humor, but she knew better—her clumsiness wasn’t brought on by the two glasses of wine she had drunk with dinner. She suddenly realized that she had been ignoring some symptoms that she should have recognized.
The next day, she consulted with one of her colleagues, who agreed that her own tentative diagnosis was probably correct: Her symptoms fit those of multiple sclerosis. She had experienced fleeting problems with double vision, she sometimes felt unsteady on her feet, and she occasionally noticed tingling sensations in her right hand. None of these symptoms was serious, and they lasted for only a short while, so she ignored them—or perhaps denied to herself that they were important.
A few weeks after Dr. C.’s death twenty-three years later, a group of medical students and neurological residents gathered in an autopsy room at the medical school. Dr. D., the school’s neuropathologist, displayed a stainless-steel tray on which were lying a brain and a spinal cord. “These belonged to Dr. C.,” he said. “Several years ago she donated her organs to the medical school.” Everyone looked at the brain more intently, knowing that it had animated an esteemed clinician and teacher whom they all knew by reputation, if not personally. Dr. D. led his audience to a set of light boxes on the wall, to which several MRI scans had been clipped. He pointed out some white spots that appeared on one scan. “This scan clearly shows some white-matter lesions, but they are gone on the next one, taken six months later. And here is another one, but it’s gone on the next scan. The immune system attacked the myelin sheaths in a particular region, and then glial cells cleaned up the debris. MRI doesn’t show the lesions then, but the axons can no longer conduct their messages.”
He put on a pair of surgical gloves, picked up Dr. C.’s brain, and cut it in several slices. He picked one up. “Here, see this?” He pointed out a spot of discoloration in a band of white matter. “This is a sclerotic plaque—a patch that feels harder than the surrounding tissue. There are many of them, located throughout the brain and spinal cord, which is why the disease is called multiple sclerosis.” He picked up the spinal cord, felt along its length with his thumb and forefinger, and then stopped and said, “Yes, I can feel a plaque right here.”
Dr. D. put the spinal cord down and said, “Who can tell me the etiology of this disorder?”
One of the students spoke up. “It’s an autoimmune disease. The immune system gets sensitized to the body’s own myelin protein and periodically attacks it, causing a variety of different neurological symptoms. Some say that a childhood viral illness somehow causes the immune system to start seeing the protein as foreign.”
“That’s right,” said Dr. D. “The primary criterion for the diagnosis of multiple sclerosis is the presence of neurological symptoms disseminated in time and space. The symptoms don’t all occur at once, and they can be caused only by damage to several different parts of the nervous system, which means that they can’t be the result of a stroke.”
As their name indicates, microglia are the smallest of the glial cells. Like some types of astrocytes, they act as phagocytes, engulfing and breaking down dead and dying neurons. But, in addition, they serve as one of the representatives of the immune system in the brain, protecting the brain from invading microorganisms. They are primarily responsible for the inflammatory reaction in response to brain damage.
SCHWANN CELLS
In the central nervous system the oligodendrocytes support axons and produce myelin. In the peripheral nervous system the Schwann cells perform the same functions. Most axons in the PNS are myelinated. The myelin sheath occurs in segments, as it does in the CNS; each segment consists of a single Schwann cell, wrapped many times around the axon. In the CNS the oligodendrocytes grow a number of paddle-shaped processes that wrap around a number of axons. In the PNS a Schwann cell provides myelin for only one axon, and the entire Schwann cell—not merely a part of it—surrounds the axon. (See Figure 2.11b . )
Schwann cells also differ from their CNS counterparts, the oligodendrocytes, in an important way. As we saw, a nerve consists of a bundle of many myelinated axons, all covered in a sheath of tough, elastic connective tissue. If damage occurs to such a nerve, Schwann cells aid in the digestion of the dead and dying axons. Then the Schwann cells arrange themselves in a series of cylinders that act as guides for regrowth of the axons. The distal portions of the severed axons die, but the stump of each severed axon grows sprouts, which then spread in all directions. If one of these sprouts encounters a cylinder provided by a Schwann cell, the sprout will grow through the tube quickly (at a rate of up to 3–4 mm a day), while the other, nonproductive sprouts wither away. If the cut ends of the nerve are still located close enough to each other, the axons will reestablish connections with the muscles and sense organs they previously served.
Unfortunately, the glial cells of the CNS are not as cooperative as the supporting cells of the PNS. If axons in the brain or spinal cord are damaged, new sprouts will form, as in the PNS. However, the budding axons encounter scar tissue produced by the astrocytes, and they cannot penetrate this barrier. Even if the sprouts could get through, the axons would not reestablish their original connections without guidance similar to that provided by the Schwann cells of the PNS. During development, axons have two modes of growth. The first mode causes them to elongate so that they reach their target, which could be as far away as the other end of the brain or spinal cord. Schwann cells provide this signal to injured axons. The second mode causes axons to stop elongating and begin sprouting terminal buttons because they have reached their target. Liuzzi and Lasek ( 1987 ) found that even when astrocytes do not produce scar tissue, they appear to produce a chemical signal that instructs regenerating axons to begin the second mode of growth: to stop elongating and start sprouting terminal buttons. Thus, the difference in the regenerative properties of axons in the CNS and the PNS results from differences in the characteristics of the supporting cells, not from differences in the axons.
There is another difference between oligodendrocytes of the CNS and Schwann cells of the PNS: the chemical composition of the myelin protein they produce. The immune system of someone with multiple sclerosis attacks only the myelin protein produced by oligodendrocytes; thus, the myelin of the peripheral nervous system is spared.
The Blood–Brain Barrier
Over one hundred years ago, Paul Ehrlich discovered that if a blue dye is injected into an animal’s bloodstream, all tissues except the brain and spinal cord will be tinted blue. However, if the same dye is injected into the fluid-filled ventricles of the brain, the blue color will spread throughout the CNS (Bradbury, 1979 ). This experiment demonstrates that a barrier exists between the blood and the fluid that surrounds the cells of the brain: the blood–brain barrier .
Some substances can cross the blood–brain barrier; others cannot. Thus, it is selectively permeable (per, “through”; meare, “to pass”). In most of the body the cells that line the capillaries do not fit together absolutely tightly. Small gaps are found between them that permit the free exchange of most substances between the blood plasma and the fluid outside the capillaries that surrounds the cells of the body. In the central nervous system the capillaries lack these gaps; therefore, many substances cannot leave the blood. Thus, the walls of the capillaries in the brain constitute the blood–brain barrier. (See Figure 2.12 . ) Other substances must be actively transported through the capillary walls by special proteins. For example, glucose transporters bring the brain its fuel, and other transporters rid the brain of toxic waste products (Rubin and Staddon, 1999 ; Zlokovic, 2008 ).
What is the function of the blood–brain barrier? As we will see, transmission of messages from place to place in the brain depends on a delicate balance between substances within neurons and those in the extracellular fluid that surrounds them. If the composition of the extracellular fluid is changed even slightly, the transmission of these messages will be disrupted, which means that brain functions will be disrupted. The presence of the blood–brain barrier makes it easier to regulate the composition of this fluid. In addition, many of the foods that we eat contain chemicals that would interfere with the transmission of information between neurons. The blood–brain barrier prevents these chemicals from reaching the brain.
FIGURE 2.12 The Blood–Brain Barrier
This figure shows that (a) the cells that form the walls of the capillaries in the body outside the brain have gaps that permit the free passage of substances into and out of the blood, and (b) the cells that form the walls of the capillaries in the brain are tightly joined.
The blood–brain barrier is not uniform throughout the nervous system. In several places the barrier is relatively permeable, allowing substances that are excluded elsewhere to cross freely. For example, the area postrema is a part of the brain that controls vomiting. The blood–brain barrier is much weaker there, permitting neurons in this region to detect the presence of toxic substances in the blood. (A barrier around the area postrema prevents substances from diffusing from this region into the rest of the brain.) A poison that enters the circulatory system from the stomach can thus stimulate the area postrema to initiate vomiting. If the organism is lucky, the poison can be expelled from the stomach before causing too much damage.
SECTION SUMMARY: Cells of the Nervous System
Neurons are the most important cells of the nervous system. The central nervous system (CNS) includes the brain and spinal cord; the peripheral nervous system (PNS) includes nerves and some sensory organs.
Neurons have four principal parts: dendrites, soma (cell body), axon, and terminal buttons. They communicate by means of synapses, junctions between the terminal buttons of one neuron and the somatic or dendritic membrane of another. When an action potential travels down an axon, its terminal buttons secrete a chemical that has either an excitatory or an inhibitory effect on the neurons with which they communicate. Ultimately, the effects of these excitatory and inhibitory synapses cause behavior, in the form of muscular contractions.
Neurons contain a quantity of cytoplasm, enclosed in a membrane. Embedded in the membrane are protein molecules that have special functions, such as the detection of hormones or neurotransmitters or transport of particular substances into and out of the cell. The cytoplasm contains the nucleus, which contains the genetic information; the nucleolus (located in the nucleus), which manufactures ribosomes; the ribosomes, which serve as sites of protein synthesis; the endoplasmic reticulum, which serves as a storage reservoir and as a channel for transportation of chemicals through the cytoplasm; the Golgi apparatus, which wraps substances that the cell secretes in a membrane; the lysosomes, which contain enzymes that destroy waste products; microtubules and other protein fibers, which compose the cytoskeleton and help to transport chemicals from place to place; and the mitochondria, which serve as the location for most of the chemical reactions through which the cell extracts energy from nutrients. Recent evidence indicates that only a small proportion of the human genome is devoted to the production of protein; the rest (formerly called “junk” DNA) is involved in the production of non-coding RNA, which has a variety of functions.
Neurons are supported by the glial cells of the central nervous system and the supporting cells of the peripheral nervous system. In the CNS, astrocytes provide support and nourishment, regulate the composition of the fluid that surrounds neurons, and remove debris and form scar tissue in the event of tissue damage. Microglia are phagocytes that serve as the representatives of the immune system. Oligodendrocytes form myelin, the substance that insulates axons, and also support unmyelinated axons. In the PNS, support and myelin are provided by the Schwann cells.
In most organs, molecules freely diffuse between the blood within the capillaries that serve them and the extracellular fluid that bathes their cells. The molecules pass through gaps between the cells that line the capillaries. The walls of the capillaries of the CNS lack these gaps; consequently, fewer substances can enter or leave the brain across the blood–brain barrier.
■ THOUGHT QUESTION
· The fact that the mitochondria in our cells were originally microorganisms that infected our very remote ancestors points out that evolution can involve interactions between two or more species. Many species have other organisms living inside them; in fact, the bacteria in our intestines are necessary for our good health. Some microorganisms can exchange genetic information, so adaptive mutations that develop in one species can be adopted by another. Is it possible that some of the features of the cells of our nervous system were bequeathed to our ancestors by other species?
Communication Within a Neuron
This section describes the nature of communication within a neuron—the way an action potential is sent from the cell body down the axon to the terminal buttons, informing them to release some neurotransmitter. The details of synaptic transmission—the communication between neurons—will be described in the next section. As we will see in this section, an action potential consists of a series of alterations in the membrane of the axon that permit various substances to move between the interior of the axon and the fluid surrounding it. These exchanges produce electrical currents. To see an interactive animation of the information presented in the following section,
Neural Communication: An Overview
Before I begin my discussion of the action potential, let’s step back and see how neurons can interact to produce a useful behavior. We begin by examining a simple assembly of three neurons and a muscle that control a withdrawal reflex. In the next two figures (and in subsequent figures that illustrate simple neural circuits), multipolar neurons are depicted in shorthand fashion as several-sided stars. The points of these stars represent dendrites, and only one or two terminal buttons are shown at the end of the axon. The sensory neuron in this example detects painful stimuli. When its dendrites are stimulated by a noxious stimulus (such as contact with a hot object), it sends messages down the axon to the terminal buttons, which are located in the spinal cord. (You will recognize this cell as a unipolar neuron; see Figure 2.13 . ) The terminal buttons of the sensory neuron release a neurotransmitter that excites the interneuron, causing it to send messages down its axon. The terminal buttons of the interneuron release a neurotransmitter that excites the motor neuron, which sends messages down its axon. The axon of the motor neuron joins a nerve and travels to a muscle. When the terminal buttons of the motor neuron release their neurotransmitter, the muscle cells contract, causing the hand to move away from the hot object. (Look again at Figure 2.13 .)
So far, all of the synapses have had excitatory effects. Now let us complicate matters a bit to see the effect of inhibitory synapses. Suppose you have removed a hot casserole from the oven. As you start walking over to the table to put it down, the heat begins to penetrate the rather thin potholders you are using. The pain caused by the heat triggers a withdrawal reflex that tends to make you drop the casserole. Yet you manage to keep hold of it long enough to get to the table and put it down. What prevented your withdrawal reflex from making you drop the casserole on the floor?
FIGURE 2.13 A Withdrawal Reflex
The figure shows a simple example of a useful function of the nervous system. The painful stimulus causes the hand to pull away from the hot iron.
The pain from the hot casserole increases the activity of excitatory synapses on the motor neurons, which tends to cause the hand to pull away from the casserole. However, this excitation is counteracted by inhibition, supplied by another source: the brain. The brain contains neural circuits that recognize what a disaster it would be if you dropped the casserole on the floor. These neural circuits send information to the spinal cord that prevents the withdrawal reflex from making you drop the dish.
Figure 2.14 shows how this information reaches the spinal cord. As you can see, an axon from a neuron in the brain reaches the spinal cord, where its terminal buttons form synapses with an inhibitory interneuron. When the neuron in the brain becomes active, its terminal buttons excite this inhibitory interneuron. The inter-neuron releases an inhibitory neurotransmitter, which decreases the activity of the motor neuron, blocking the withdrawal reflex. This circuit provides an example of a contest between two competing tendencies: to drop the casserole and to hold onto it. (See Figure 2.14 . )
FIGURE 2.14 The Role of Inhibition
Inhibitory signals arising from the brain can prevent the withdrawal reflex from causing the person to drop the casserole.
Of course, reflexes are more complicated than this description, and the mechanisms that inhibit them are even more so. And thousands of neurons are involved in this process. The five neurons shown in Figure 2.14 represent many others: Dozens of sensory neurons detect the hot object, hundreds of interneurons are stimulated by their activity, hundreds of motor neurons produce the contraction—and thousands of neurons in the brain must become active if the reflex is to be inhibited. Yet this simple model provides an overview of the process of neural communication, which is described in more detail later in this chapter.
Measuring Electrical Potentials of Axons
Let’s examine the nature of the message that is conducted along the axon. To do so, we obtain an axon that is large enough to work with. Fortunately, nature has provided the neuroscientist with the giant squid axon (the giant axon of a squid, not the axon of a giant squid!). This axon is about 0.5 mm in diameter, which is hundreds of times larger than the largest mammalian axon. (This large axon controls an emergency response: sudden contraction of the mantle, which squirts water through a jet and propels the squid away from a source of danger.) We place an isolated giant squid axon in a dish of seawater, in which it can exist for a day or two.
To measure the electrical charges generated by an axon, we will need to use a pair of electrodes. Electrodes are electrical conductors that provide a path for electricity to enter or leave a medium. One of the electrodes is a simple wire that we place in the seawater. The other one, which we use to record the message from the axon, has to be special. Because even a giant squid axon is rather small, we must use a tiny electrode that will record the membrane potential without damaging the axon. To do so, we use a microelectrode.
A microelectrode is simply a very small electrode, which can be made of metal or glass. In this case we will use one made of thin glass tubing, which is heated and drawn down to an exceedingly fine point, less than a thousandth of a millimeter in diameter. Because glass will not conduct electricity, the glass microelectrode is filled with a liquid that conducts electricity, such as a solution of potassium chloride.
We place the wire electrode in the seawater and insert the microelectrode into the axon. (See Figure 2.15a . ) As soon as we do so, we discover that the inside of the axon is negatively charged with respect to the outside; the difference in charge being 70 mV (millivolts, or thousandths of a volt). Thus, the inside of the membrane is –70 mV. This electrical charge is called the membrane potential . The term potentialrefers to a stored-up source of energy—in this case, electrical energy. For example, a flashlight battery that is not connected to an electrical circuit has a potential charge of 1.5 V between its terminals. If we connect a light bulb to the terminals, the potential energy is tapped and converted into radiant energy (light). (See Figure 2.15b . ) Similarly, if we connect our electrodes—one inside the axon and one outside it—to a very sensitive voltmeter, we will convert the potential energy to movement of the meter’s needle. Of course, the potential electrical energy of the axonal membrane is very weak in comparison with that of a flashlight battery.
FIGURE 2.15 Measuring Electrical Charge
The figure shows (a) a voltmeter detecting the charge across a membrane of an axon and (b) a light bulb detecting the charge across the terminals of a battery.
As we will see, the message that is conducted down the axon consists of a brief change in the membrane potential. However, this change occurs very rapidly—too rapidly for us to see if we were using a voltmeter. Therefore, to study the message, we will use an oscilloscope . This device, like a voltmeter, measures voltages, but it also produces a record of these voltages, graphing them as a function of time. These graphs are displayed on a screen, much like the one found in a television. The vertical axis represents voltage, and the horizontal axis represents time, going from left to right.
FIGURE 2.16 Studying the Axon
The figure shows the means by which an axon can be stimulated while its membrane potential is being recorded.
Once we insert our microelectrode into the axon, the oscilloscope draws a straight horizontal line at –70 mV, as long as the axon is not disturbed. This electrical charge across the membrane is called, quite appropriately, the resting potential . Now let us disturb the resting potential and see what happens. To do so, we will use another device—an electrical stimulator that allows us to alter the membrane potential at a specific location. (See Figure 2.16 . ) The stimulator can pass current through another microelectrode that we have inserted into the axon. Because the inside of the axon is negative, a positive charge applied to the inside of the membrane produces a depolarization . That is, it takes away some of the electrical charge across the membrane near the electrode, reducing the membrane potential.
Let us see what happens to an axon when we artificially change the membrane potential at one point. Figure 2.17 shows a graph drawn by an oscilloscope that has been monitoring the effects of brief depolarizing stimuli. The graphs of the effects of these separate stimuli are superimposed on the same drawing so that we can compare them. We deliver a series of depolarizing stimuli, starting with a very weak stimulus (number 1) and gradually increasing their strength. Each stimulus briefly depolarizes the membrane potential a little more. Finally, after we present depolarization number 4, the membrane potential suddenly reverses itself, so the inside becomes positive (and the outside becomes negative). The membrane potential quickly returns to normal, but first it overshoots the resting potential, becoming hyperpolarized —more polarized than normal—for a short time. The whole process takes about 2 msec (milliseconds). (See Figure 2.17 . )
FIGURE 2.17 An Action Potential
These results would be seen on an oscilloscope screen if depolarizing stimuli of varying intensities were delivered to the axon shown in Figure 2.16 .
This phenomenon, a very rapid reversal of the membrane potential, is called the action potential . It constitutes the message carried by the axon from the cell body to the terminal buttons. The voltage level that triggers an action potential—which was achieved only by depolarizing shock number 4—is called the threshold of excitation .
The Membrane Potential: Balance of Two Forces
To understand what causes the action potential to occur, we must first understand the reasons for the existence of the membrane potential. As we will see, this electrical charge is the result of a balance between two opposing forces: diffusion and electrostatic pressure.
THE FORCE OF DIFFUSION
When a spoonful of sugar is carefully poured into a container of water, it settles to the bottom. After a time the sugar dissolves, but it remains close to the bottom of the container. After a much longer time (probably several days) the molecules of sugar distribute themselves evenly throughout the water, even if no one stirs the liquid. The process whereby molecules distribute themselves evenly throughout the medium in which they are dissolved is called diffusion .
When there are no forces or barriers to prevent them from doing so, molecules will diffuse from regions of high concentration to regions of low concentration. Molecules are constantly in motion, and their rate of movement is proportional to the temperature. Only at absolute zero [0 K (kelvin) = −273.15°C = −459.7°F] do molecules cease their random movement. At all other temperatures they move about, colliding and veering off in different directions, thus pushing one another away. The result of these collisions in the example of sugar and water is to force sugar molecules upward (and to force water molecules downward), away from the regions in which they are most concentrated.
THE FORCE OF ELECTROSTATIC PRESSURE
When some substances are dissolved in water, they split into two parts, each with an opposing electrical charge. Substances with this property are called electrolytes ; the charged particles into which they decompose are called ions . Ions are of two basic types: Cations have a positive charge, and anions have a negative charge. For example, when sodium chloride (NaCl, table salt) is dissolved in water, many of the molecules split into sodium cations (Na+) and chloride anions (Cl−). (I find that the easiest way to keep the terms cation and anion straight is to think of the cation’s plus sign as a cross and remember the superstition of a black cat crossing your path.)
As you have undoubtedly learned, particles with the same kind of charge repel each other (+ repels +, and − repels −), but particles with different charges are attracted to each other (+ and − attract). Thus, anions repel anions, cations repel cations, but anions and cations attract each other. The force exerted by this attraction or repulsion is called electrostatic pressure . Just as the force of diffusion moves molecules from regions of high concentration to regions of low concentration, electrostatic pressure moves ions from place to place: Cations are pushed away from regions with an excess of cations, and anions are pushed away from regions with an excess of anions.
IONS IN THE EXTRACELLULAR AND INTRACELLULAR FLUID
The fluid within cells ( intracellular fluid ) and the fluid surrounding them ( extracellular fluid ) contain different ions. The forces of diffusion and electrostatic pressure contributed by these ions give rise to the membrane potential. Because the membrane potential is produced by a balance between the forces of diffusion and electrostatic pressures, understanding what produces this potential requires that we know the concentration of the various ions in the extracellular and intracellular fluids.
There are several important ions in these fluids. I will discuss four of them here: organic anions (symbolized by A−), chloride ions (Cl−), sodium ions (Na+), and potassium ions (K+). The Latin words for sodium and potassium are natrium and kalium; hence, they are abbreviated Na and K, respectively. Organic anions—negatively charged proteins and intermediate products of the cell’s metabolic processes—are found only in the intracellular fluid. Although the other three ions are found in both the intracellular and extracellular fluids, K+ is found predominantly in the intracellular fluid, whereas Na+and Cl− are found predominantly in the extracellular fluid. The sizes of the boxes in Figure 2.18 indicate the relative concentrations of these four ions. (See Figure 2.18 . ) The easiest way to remember which ion is found where is to recall that the fluid that surrounds our cells is similar to seawater, which is predominantly a solution of salt, NaCl. The primitive ancestors of our cells lived in the ocean; thus, the seawater was their extracellular fluid. Our extracellular fluid thus resembles seawater, produced and maintained by regulatory mechanisms that are described in Chapter 12 .
Let us consider the ions in Figure 2.18 , examining the forces of diffusion and electrostatic pressure exerted on each and reasoning why each is located where it is. A−, the organic anion, is unable to pass through the membrane of the axon; therefore, although the presence of this ion within the cell contributes to the membrane potential, it is located where it is because the membrane is impermeable to it.
FIGURE 2.18 Control of the Membrane Potential
The figure shows the relative concentration of some important ions inside and outside the neuron and the forces acting on them.
The potassium ion K+ is concentrated within the axon; thus, the force of diffusion tends to push it out of the cell. However, the outside of the cell is charged positively with respect to the inside, so electrostatic pressure tends to force this cation inside. Thus, the two opposing forces balance, and potassium ions tend to remain where they are. (Refer again to Figure 2.18 .)
The chloride ion Cl− is in greatest concentration outside the axon. The force of diffusion pushes this ion inward. However, because the inside of the axon is negatively charged, electrostatic pressure pushes this anion outward. Again, two opposing forces balance each other. (Look again at Figure 2.18 .)
The sodium ion Na+ is also in greatest concentration outside the axon, so it, like Cl−, is pushed into the cell by the force of diffusion. But unlike chloride, the sodium ion is positively charged. Therefore, electrostatic pressure does not prevent Na+ from entering the cell; indeed, the negative charge inside the axon attractsNa+. (Look once more at Figure 2.18 .)
How can Na+ remain in greatest concentration in the extracellular fluid, despite the fact that both forces (diffusion and electrostatic pressure) tend to push it inside? The answer is this: Another force, provided by the sodium–potassium pump, continuously pushes Na+ out of the axon. The sodium–potassium pump consists of a large number of protein molecules embedded in the membrane, driven by energy provided by molecules of ATP produced by the mitochondria. These molecules, known as sodium–potassium transporters , exchange Na+ for K+, pushing three sodium ions out for every two potassium ions they push in. (See Figure 2.19 . )
Because the membrane is not very permeable to Na+, sodium–potassium transporters very effectively keep the intracellular concentration of Na+ low. By transporting K+ into the cell, they also increase the intracellular concentration of K+ a small amount. The membrane is approximately 100 times more permeable to K+ than to Na+, so the increase is slight; but, as we will see when we study the process of neural inhibition later in this chapter, it is very important. The transporters that make up the sodium–potassium pump use considerable energy: Up to 40 percent of a neuron’s metabolic resources are used to operate them. Neurons, muscle cells, glia—in fact, most cells of the body—have sodium–potassium transporters in their membrane.
The Action Potential
As we saw, the forces of both diffusion and electrostatic pressure tend to push Na+ into the cell. However, the membrane is not very permeable to this ion, and sodium–potassium transporters continuously pump out Na+, keeping the intracellular level of Na+ low. But imagine what would happen if the membrane suddenly became permeable to Na+. The forces of diffusion and electrostatic pressure would cause Na+ to rush into the cell. This sudden influx (inflow) of positively charged ions would drastically change the membrane potential. Indeed, experiments have shown that this mechanism is precisely what causes the action potential: A brief increase in the permeability of the membrane to Na+ (allowing these ions to rush into the cell) is immediately followed by a transient increase in the permeability of the membrane to K+(allowing these ions to rush out of the cell). What is responsible for these transient increases in permeability?
FIGURE 2.19 A Sodium–Potassium Transporter
These transporters are found in the cell membrane.
We already saw that one type of protein molecule embedded in the membrane—the sodium–potassium transporter—actively pumps sodium ions out of the cell and pumps potassium ions into it. Another type of protein molecule provides an opening that permits ions to enter or leave the cells. These molecules provide ion channels , which contain passages (“pores”) that can open or close. When an ion channel is open, a particular type of ion can flow through the pore and thus can enter or leave the cell. (See Figure 2.20 . ) Neural membranes contain many thousands of ion channels. For example, the giant squid axon contains several hundred sodium channels in each square micrometer of membrane. (There are one million square micrometers in a square millimeter; thus, a patch of axonal membrane the size of a lowercase letter o in this book would contain several hundred million sodium channels.) Each sodium channel can admit up to 100 million ions per second when it is open. Thus, the permeability of a membrane to a particular ion at a given moment is determined by the number of ion channels that are open.
FIGURE 2.20 Ion Channels
When ion channels are open, ions can pass through them, entering or leaving the cell.
The following numbered paragraphs describe the movements of ions through the membrane during the action potential. The numbers in the figure correspond to the numbers of the paragraphs that follow. (See Figure 2.21 . )
FIGURE 2.21 Ion Movements During the Action Potential
The shaded box at the top shows the opening of sodium channels at the threshold of excitation, their refractory condition at the peak of the action potential, and their resetting when the membrane potential returns to normal.
· 1. As soon as the threshold of excitation is reached, the sodium channels in the membrane open, and Na+ rushes in, propelled by the forces of diffusion and electrostatic pressure. The opening of these channels is triggered by reduction of the membrane potential (depolarization); they open at the point at which an action potential begins: the threshold of excitation. Because these channels are opened by changes in the membrane potential, they are called voltage-dependent ion channels . The influx of positively charged sodium ions produces a rapid change in the membrane potential, from −70 mV to + 40 mV.
· 2. The membrane of the axon contains voltage-dependent potassium channels, but these channels are less sensitive than voltage-dependent sodium channels. That is, they require a greater level of depolarization before they begin to open. Thus, they begin to open later than the sodium channels.
FIGURE 2.22 Permeability to Ions During the Action Potential
The graph shows changes in the permeability of the membrane of an axon to Na+ and K+ during the action potential.
· 3. At about the time the action potential reaches its peak (in approximately 1 msec), the sodium channels become refractory—the channels become blocked and cannot open again until the membrane once more reaches the resting potential. At this time, no more Na+ can enter the cell.
· 4. By now, the voltage-dependent potassium channels in the membrane are open, letting K+ ions move freely through the membrane. At this time, the inside of the axon is positively charged, so K+ is driven out of the cell by diffusion and by electrostatic pressure. This outflow of cations causes the membrane potential to return toward its normal value. As it does so, the potassium channels begin to close again.
· 5. Once the membrane potential returns to normal, the sodium channels reset so that another depolarization can cause them to open again.
· 6. The membrane actually overshoots its resting value (−70 mV) and only gradually returns to normal as the potassium channels finally close. Eventually, sodium–potassium transporters remove the Na+ions that leaked in and retrieve the K+ ions that leaked out.
Figure 2.22 illustrates the changes in permeability of the membrane to sodium and potassium ions during the action potential. (See Figure 2.22 . )
How much ionic flow is there? The increased permeability of the membrane to Na+ is brief, and diffusion over any appreciable distance takes some time. Thus, when I say, “Na+ rushes in,” I do not mean that the axoplasm becomes flooded with Na+. At the peak of the action potential a very thin layer of fluid immediately inside the axon becomes full of newly arrived Na+ ions; this amount is indeed enough to reverse the membrane potential. However, not enough time has elapsed for these ions to fill the entire axon. Before that event can take place, the Na+ channels close, and K+ starts flowing out.
Experiments have shown that an action potential temporarily increases the number of Na+ ions inside the giant squid axon by 0.0003 percent. Although the concentration just inside the membrane is high, the total number of ions entering the cell is very small relative to the number already there. This means that, on a short-term basis, sodium–potassium transporters are not very important. The few Na+ ions that manage to leak in diffuse into the rest of the axoplasm, and the slight increase in Na+ concentration is hardly noticeable. However, sodium–potassium transporters are important on a long-term basis. Without the activity of sodium–potassium transporters, the concentration of sodium ions in the axoplasm would eventually increase enough that the axon would no longer be able to function.
Conduction of the Action Potential
Now that we have a basic understanding of the resting membrane potential and the production of the action potential, we can consider the movement of the message down the axon, or conduction of the action potential. To study this phenomenon, we again make use of the giant squid axon. We attach an electrical stimulator to an electrode at one end of the axon and place recording electrodes, attached to oscilloscopes, at different distances from the stimulating electrode. Then we apply a depolarizing stimulus to the end of the axon and trigger an action potential. We record the action potential from each of the electrodes, one after the other. Thus, we see that the action potential is conducted down the axon. As the action potential travels, it remains constant in size. (See Figure 2.23 . )
This experiment establishes a basic law of axonal conduction: the all-or-none law . This law states that an action potential either occurs or does not occur; and, once triggered, it is transmitted down the axon to its end. An action potential always remains the same size, without growing or diminishing. And when an action potential reaches a point where the axon branches, it splits but does not diminish in size. An axon will transmit an action potential in either direction, or even in both directions, if it is started in the middle of the axon’s length. However, because action potentials in living animals start at the end attached to the soma, axons normally carry one-way traffic.
As you know, the strength of a muscular contraction can vary from very weak to very forceful, and the strength of a stimulus can vary from barely detectable to very intense. We know that the occurrence of action potentials in axons controls the strength of muscular contractions and represents the intensity of a physical stimulus. But if the action potential is an all-or-none event, how can it represent information that can vary in a continuous fashion? The answer is simple: A single action potential is not the basic element of information; rather, variable information is represented by an axon’s rate of firing. (In this context, firing refers to the production of action potentials.) A high rate of firing causes a strong muscular contraction, and a strong stimulus (such as a bright light) causes a high rate of firing in axons that serve the eyes. Thus, the all-or-none law is supplemented by the rate law . (See Figure 2.24 . )
FIGURE 2.23 Conduction of the Action Potential
When an action potential is triggered, its size remains undiminished as it travels down the axon. The speed of conduction can be calculated from the delay between the stimulus and the action potential.
Recall that all but the smallest axons in mammalian nervous systems are myelinated; segments of the axons are covered by a myelin sheath produced by the oligodendrocytes of the CNS or the Schwann cells of the PNS. These segments are separated by portions of naked axon, the nodes of Ranvier. Conduction of an action potential in a myelinated axon is somewhat different from conduction in an unmyelinated axon.
Schwann cells and the oligodendrocytes of the CNS wrap tightly around the axon, leaving no measurable extracellular fluid between them and the axon. The only place where a myelinated axon comes into contact with the extracellular fluid is at a node of Ranvier, where the axon is naked. In the myelinated areas there can be no inward flow of Na+ when the sodium channels open because there is no extracellular sodium. The axon conducts the electrical disturbance from the action potential to the next node of Ranvier. The disturbance is conducted passively, the way an electrical signal is conducted through an insulated cable. The disturbance gets smaller as it passes down the axon, but it is still large enough to trigger a new action potential at the next node. (This decrease in the size of the disturbance is called decremental conduction.) The action potential gets retriggered, or repeated, at each node of Ranvier, and the electrical disturbance that results is conducted decrementally along the myelinated area to the next node. Transmission of this message, hopping from node to node, is called saltatory conduction , from the Latin saltare, “to dance.” (See Figure 2.25 . )
FIGURE 2.24 The Rate Law
The strength of a stimulus is represented by the rate of firing of an axon. The size of each action potential is always constant.
Saltatory conduction confers two advantages. The first is economic. Sodium ions enter axons during action potentials, and these ions must eventually be removed. Sodium–potassium transporters must be located along the entire length of unmyelinated axons because Na+ enters everywhere. However, because Na+ can enter myelinated axons only at the nodes of Ranvier, much less gets in, and consequently much less has to be pumped out again. Therefore, myelinated axons expend much less energy to maintain their sodium balance.
The second advantage to myelin is speed. Conduction of an action potential is faster in a myelinated axon because the transmission between the nodes is very fast. Increased speed enables an animal to react faster and (undoubtedly) to think faster. One of the ways to increase the speed of conduction is to increase size. Because it is so large, the unmyelinated squid axon, with a diameter of 500 μm, achieves a conduction velocity of approximately 35 m/sec (meters per second). However, a myelinated cat axon achieves the same speed with a diameter of a mere 6 μm. The fastest myelinated axon, 20 μm in diameter, can conduct action potentials at a speedy 120 m/sec, or 432 km/h (kilometers per hour). At that speed a signal can get from one end of an axon to the other without much delay.
FIGURE 2.25 Saltatory Conduction
The figure shows propagation of an action potential down a myelinated axon.
SECTION SUMMARY: Communication Within a Neuron
The withdrawal reflex illustrates how neurons can be connected to accomplish useful behaviors. The circuit responsible for this reflex consists of three sets of neurons: sensory neurons, interneurons, and motor neurons.
The reflex can be suppressed when neurons in the brain activate inhibitory interneurons that form synapses with the motor neurons.
The message that is conducted down an axon is called an action potential. The membranes of all cells of the body are electrically charged, but only axons can produce action potentials. The resting membrane potential occurs because various ions are located in different concentrations in the fluid inside and outside the cell. The extracellular fluid (like seawater) is rich in Na+ and Cl−, and the intracellular fluid is rich in K+ and various organic anions, designated as A−.
The cell membrane is freely permeable to water, but its permeability to various ions—in particular, Na+and K+—is regulated by ion channels. When the membrane potential is at its resting value (–70 mV), the voltage-dependent sodium and potassium channels are closed. Some Na+ continuously leaks into the axon but is promptly forced out of the cell again by the sodium–potassium transporters (which also pump potassium into the axon). When an electrical stimulator depolarizes the membrane of the axon so that its potential reaches the threshold of excitation, voltage-dependent sodium channels open, and Na+ rushes into the cell, driven by the force of diffusion and by electrostatic pressure. The entry of these positively charged ions further reduces the membrane potential and, indeed, causes it to reverse, so the inside becomes positive. The opening of the sodium channels is temporary; they soon close again. The depolarization caused by the influx of Na+ activates voltage-dependent potassium channels, and K+ leaves the axon, traveling down its concentration gradient. This efflux (outflow) of K+ quickly brings the membrane potential back to its resting value.
Because an action potential of a given axon is an all-or-none phenomenon, neurons represent intensity by their rate of firing. The action potential normally begins at one end of the axon, where the axon attaches to the soma. The action potential travels continuously down unmyelinated axons, remaining constant in size, until it reaches the terminal buttons. (If the axon divides, an action potential continues down each branch.) In myelinated axons, ions can flow through the membrane only at the nodes of Ranvier, because the axons are covered everywhere else with myelin, which isolates them from the extracellular fluid. Thus, the action potential is conducted passively from one node of Ranvier to the next. When the electrical message reaches a node, voltage-dependent sodium channels open, and a new action potential is triggered. This mechanism saves a considerable amount of energy because sodium–potassium transporters are not needed along the myelinated portions of the axon, and saltatory conduction is faster.
■ THOUGHT QUESTION
· The evolution of the human brain, with all its complexity, depended on many apparently trivial mechanisms. For example, what if cells had not developed the ability to manufacture myelin? Unmyelinated axons must be very large if they are to transmit action potentials rapidly. How big would the human brain have to be if oligodendrocytes did not produce myelin? Could the human brain as we know it have evolved without myelin?
Communication Between Neurons
Now that you know about the basic structure of neurons and the nature of the action potential, it is time to describe the ways in which neurons can communicate with each other. These communications make it possible for circuits of neurons to gather sensory information, make plans, and initiate behaviors.
The primary means of communication between neurons is synaptic transmission—the transmission of messages from one neuron to another through a synapse. As we saw, these messages are carried by neurotransmitters, released by terminal buttons. These chemicals diffuse across the fluid-filled gap between the terminal buttons and the membranes of the neurons with which they form synapses. As we will see in this section, neurotransmitters produce
postsynaptic potentials
—brief depolarizations or hyperpolarizations—that increase or decrease the rate of firing of the axon of the postsynaptic neuron. To see an interactive animation of the information presented in the following section,
Neurotransmitters exert their effects on cells by attaching to a particular region of a receptor molecule called the binding site . A molecule of the chemical fits into the binding site the way a key fits into a lock: The shape of the binding site and the shape of the molecule of the neurotransmitter are complementary. A chemical that attaches to a binding site is called a ligand , from ligare, “to bind.” Neurotransmitters are natural ligands, produced and released by neurons. But other chemicals found in nature (primarily in plants or in the poisonous venoms of animals) can serve as ligands too. In addition, artificial ligands can be produced in the laboratory. These chemicals are discussed in Chapter 4 , which deals with drugs and their effects.
Structure of Synapses
As you have already learned, synapses are junctions between the terminal buttons at the ends of the axonal branches of one neuron and the membrane of another. Synapses can occur in three places: on dendrites, on the soma, and on other axons. These synapses are referred to as axodendritic, axosomatic, and axoaxonic. Axodendritic synapses can occur on the smooth surface of a dendrite or on dendritic spines —small protrusions that stud the dendrites of several types of large neurons in the brain. (See Figure 2.26 . )
Figure 2.27 illustrates a synapse. The presynaptic membrane , located at the end of the terminal button, faces the postsynaptic membrane , located on the neuron that receives the message (the postsynapticneuron). These two membranes face each other across the synaptic cleft , a gap that varies in size from synapse to synapse but is usually around 20 nm wide. (A nanometer, nm, is one billionth of a meter.) The synaptic cleft contains extracellular fluid, through which the neurotransmitter diffuses. A meshwork of filaments crosses the synaptic cleft and keeps the presynaptic and postsynaptic membranes in alignment. (See Figure 2.27 . )
FIGURE 2.26 Types of Synapses
Axodendritic synapses can occur on the smooth surface of a dendrite (a) or on dendritic spines (b). Axosomatic synapses occur on somatic membrane (c). Axoaxonic synapses consist of synapses between two terminal buttons (d).
As you may have noticed in Figure 2.27 , two prominent structures are located in the cytoplasm of the terminal button: mitochondria and synaptic vesicles. We also see microtubules, which are responsible for transporting material between the soma and terminal button. The presence of mitochondria implies that the terminal button needs energy to perform its functions. Synaptic vesicles are small, rounded objects in the shape of spheres or ovoids. (The term vesicle means “little bladder.”) A given terminal button can contain from a few hundred to nearly a million synaptic vesicles. Many terminal buttons contain two types of synaptic vesicles: large and small. Small synaptic vesicles (found in all terminal buttons) contain molecules of the neurotransmitter. They range in number from a few dozen to several hundred. The membrane of small synaptic vesicles consists of approximately 10,000 lipid molecules into which are inserted about 200 protein molecules. Transport proteins fill vesicles with the neurotransmitter, and trafficking proteins are involved in the release of neurotransmitter and recycling of the vesicles. Synaptic vesicles are found in greatest numbers around the part of the presynaptic membrane that faces the synaptic cleft—near the release zone , the region from which the neurotransmitter is released. In many terminal buttons we see a scattering of large, dense-core synaptic vesicles. These vesicles contain one of a number of different peptides, the functions of which are described later in this chapter. (See Figures 2.27 and 2.28 . )
FIGURE 2.27 Details of a Synapse
Small synaptic vesicles are produced in the Golgi apparatus located in the soma and are carried by fast axoplasmic transport to the terminal button. As we will see, some are also produced from recycled material in the terminal button. Large synaptic vesicles are produced only in the soma and are transported through the axoplasm to the terminal buttons.
In an electron micrograph the postsynaptic membrane under the terminal button appears somewhat thicker and more dense than the membrane elsewhere. This postsynaptic density is caused by the presence of receptors—specialized protein molecules that detect the presence of neurotransmitters in the synaptic cleft—and protein filaments that hold the receptors in place. (Look again at Figures 2.27 and 2.28 . )
FIGURE 2.28 Cross Section of a Synapse
The photograph from an electron microscope shows a cross section of a synapse. The terminal button contains many synaptic vesicles, filled with the neurotransmitter, and a single large dense-core vesicle, filled with a peptide.
(From De Camilli et al., in Synapses, edited by W. M. Cowan, T. C. Südhof, and C. F. Stevens. Baltimore, MD: Johns Hopkins University Press, 2001. Reprinted with permission.)
Release of Neurotransmitter
When action potentials are conducted down an axon (and down all of its branches), something happens inside all of the terminal buttons: A number of small synaptic vesicles located just inside the presynaptic membrane fuse with the membrane and then break open, spilling their contents into the synaptic cleft. Figure 2.29 shows a portion of a frog’s neuromuscular junction—the synapse between a terminal button and a muscle fiber. The axon has just been stimulated, and synaptic vesicles in the terminal button are in the process of releasing the neurotransmitter. Note that some vesicles are fused with the presynaptic membrane, forming the shape of an omega (Ω). (See Figure 2.29 . )
How does an action potential cause synaptic vesicles to release the neurotransmitter? The process begins when a population of synaptic vesicles become “docked” against the presynaptic membrane, ready to release their neurotransmitter into the synaptic cleft. Docking is accomplished when clusters of protein molecules attach to other protein molecules located in the presynaptic membrane. (See Figure 2.30 . )
FIGURE 2.29 Cross Section of a Synapse
The photograph from an electron microscope shows a cross section of a synapse. The omega-shaped figures are synaptic vesicles fusing with the presynaptic membranes of terminal buttons that form synapses with frog muscle.
(From Heuser, J. E., in Society for Neuroscience Symposia, Vol. II, edited by W. M. Cowan and J. A. Ferrendelli. Bethesda, MD: Society for Neuroscience, 1977. Reprinted with permission.)
FIGURE 2.30 Release of Neurotransmitter
An action potential opens calcium channels, which enter and bind with the protein embedded in the membrane of synaptic vesicles docked at the release zone. The fusion pores open, and the neurotransmitter is released into the synaptic cleft.
The release zone of the presynaptic membrane contains voltage-dependent calcium channels. When the membrane of the terminal button is depolarized by an arriving action potential, the calcium channels open. Like sodium ions, calcium ions (Ca2+) are located in highest concentration in the extracellular fluid. Thus, when the voltage-dependent calcium channels open, Ca2+ flows into the cell, propelled by electrostatic pressure and the force of diffusion. The entry of Ca2+ is an essential step; if neurons are placed in a solution that contains no calcium ions, an action potential no longer causes the release of the neurotransmitter. (Calcium transporters, similar in operation to sodium–potassium transporters, later remove the intracellular Ca2+.)
As we will see later in this chapter and in subsequent chapters of this book, calcium ions play many important roles in biological processes within cells. Calcium ions can bind with various types of proteins, changing their characteristics. Some of the calcium ions that enter the terminal button bind with the clusters of protein molecules that join the membrane of the synaptic vesicles with the presynaptic membrane. This event makes the segments of the clusters of protein molecules move apart, producing a fusion pore—a hole through both membranes that enables them to fuse together. The process of fusion takes approximately 0.1 msec. (Look again at Figure 2.30 .)
Figure 2.31 shows two photomicrographs of the presynaptic membrane, before and after the fusion pores have opened. We see the face of the presynaptic membrane as it would be viewed from the postsynaptic membrane. As you can see, the synaptic vesicles are aligned in a row along the release zone. The small bumps arranged in lines on each side of the synaptic vesicles appear to be voltage-dependent calcium channels. (See Figure 2.31 . )
Research indicates that there are three distinct pools of synaptic vesicles (Rizzoli and Betz, 2005 ). Release-ready vesicles are docked against the inside of the presynaptic membrane, ready to release their contents when an action potential arrives. These vesicles constitute less than 1 percent of the total number found in the terminal. Vesicles in the recycling pool constitute 10–15 percent of the total pool of vesicles, and those in the reserve pool make up the remaining 85–90 percent. If the axon fires at a low rate, only vesicles from the release-ready pool will be called on. If the rate of firing increases, vesicles from the recycling pool and finally from the reserve pool will release their contents.
What happens to the membrane of the synaptic vesicles after they have broken open and released the neurotransmitter they contain? It appears that many vesicles in the ready-release pool use a process known as kiss and run. These synaptic vesicles release most or all of their neurotransmitter, the fusion pore closes, and the vesicles break away from the presynaptic membrane and get filled with neurotransmitter again. Other vesicles (primarily those in the recycling pool) merge and recycle and consequently lose their identity. The membranes of these vesicles merge with the presynaptic membrane. Little buds of membrane then pinch off into the cytoplasm and become synaptic vesicles. The appropriate proteins are inserted into the membrane of these vesicles, and the vesicles are filled with molecules of the neurotransmitter. The membranes of vesicles in the reserve pool are recycled through a process of bulk endocytosis. (Endocytosis means “the process of entering a cell.”) Large pieces of the membrane of the terminal button fold inward, break off, and enter the cytoplasm. New vesicles are formed from small buds that break off of these pieces of membrane. The recycling process takes less than a second for the readily releasable pool, a few seconds for the recycling pool, and a few minutes for the reserve pool. (See Figure 2.32 . )
FIGURE 2.31 Release of Neurotransmitter
These photomicrographs show the release of neurotransmitter by a terminal button that forms a synapse with a frog muscle. The views are of the surface of the fusion zone of the terminal button. (a) Just before release. The two rows of dots are probably calcium channels. (b) During release. The larger circles are holes in the presynaptic membrane, revealing the contents of the synaptic vesicles that have fused with it.
(From Heuser, J., and Reese, T. Journal of Cell Biology, 1981, 88, 564–580. Reprinted with permission.)
FIGURE 2.32 Recycling of the Membrane of Synaptic Vesicles
After synaptic vesicles have released neurotransmitter into the synaptic cleft, the following takes place: In “kiss and run,” the vesicle fuses with the presynaptic membrane, releases the neurotransmitter, reseals, leaves the docking site, becomes refilled with the neurotransmitter, and mixes with other vesicles in the terminal button. In “merge and recycle,” the vesicle completely fuses with the postsynaptic membrane, losing its identity. Extra membrane from fused vesicles pinches off into the cytoplasm and forms vesicles, which are filled with the neurotransmitter. The membranes of vesicles in the reserve pool are recycled through a process of bulk endocytosis. Large pieces of the membrane of the terminal button fold inward, break off, and enter the cytoplasm. New vesicles are formed from small buds that break off of these pieces of membrane.
Activation of Receptors
How do molecules of the neurotransmitter produce a depolarization or hyperpolarization in the postsynaptic membrane? They do so by diffusing across the synaptic cleft and attaching to the binding sites of special protein molecules located in the postsynaptic membrane, called postsynaptic receptors . Once binding occurs, the postsynaptic receptors open neurotransmitter-dependent ion channels , which permit the passage of specific ions into or out of the cell. Thus, the presence of the neurotransmitter in the synaptic cleft allows particular ions to pass through the membrane, changing the local membrane potential.
Neurotransmitters open ion channels by at least two different methods, direct and indirect. The direct method is simpler, so I will describe it first. Figure 2.33 illustrates a neurotransmitter-dependent ion channel that is equipped with its own binding site. When a molecule of the appropriate neurotransmitter attaches to it, the ion channel opens. The formal name for this combination receptor/ion channel is an ionotropic receptor . (See Figure 2.33 . )
FIGURE 2.33 Ionotropic Receptors
The ion channel opens when a molecule of neurotransmitter attaches to the binding site. For purposes of clarity the drawing is schematic; molecules of neurotransmitter are actually much larger than individual ions.
Ionotropic receptors were first discovered in the organ that produces electrical current in Torpedo, the electric ray, where they occur in great number. (The electric ray is a fish that generates a powerful electrical current, not some kind of Star Wars weapon.) These receptors, which are sensitive to a neurotransmitter called acetylcholine, contain sodium channels. When these channels are open, sodium ions enter the cell and depolarize the membrane.
The indirect method is more complicated. Some receptors do not open ion channels directly but instead start a chain of chemical events. These receptors are called metabotropic receptors because they involve steps that require that the cell expend metabolic energy. Metabotropic receptors are located in close proximity to another protein attached to the membrane—a G protein . When a molecule of the neurotransmitter binds with the receptor, the receptor activates a G protein situated inside the membrane next to the receptor. When activated, the G protein activates an enzyme that stimulates the production of a chemical called a second messenger . (The neurotransmitter is the first messenger.) Molecules of the second messenger travel through the cytoplasm, attach themselves to nearby ion channels, and cause them to open. Compared with postsynaptic potentials produced by ionotropic receptors, those produced by metabotropic receptors take longer to begin and last longer. (See Figure 2.34 . )
The first second messenger to be discovered was cyclic AMP, a chemical that is synthesized from ATP. Since then, several other second messengers have been discovered. As you will see in later chapters, second messengers play an important role in both synaptic and nonsynaptic communication. And they can do more than open ion channels. For example, they can travel to the nucleus or other regions of the neuron and initiate biochemical changes that affect the functions of the cell. They can even turn specific genes on or off, thus initiating or terminating production of particular proteins.
FIGURE 2.34 Metabotropic Receptors
When a molecule of neurotransmitter binds with a receptor, a G protein activates an enzyme, which produces a second messenger (represented by black arrows) that opens nearby ion channels.
Postsynaptic Potentials
As I mentioned earlier, postsynaptic potentials can be either depolarizing (excitatory) or hyperpolarizing (inhibitory). What determines the nature of the postsynaptic potential at a particular synapse is not the neurotransmitter itself. Instead, it is determined by the characteristics of the postsynaptic receptors—in particular, by the particular type of ion channel they open.
As Figure 2.35 shows, four major types of neurotransmitter-dependent ion channels are found in the postsynaptic membrane: sodium (Na+), potassium (K+), chloride (Cl−), and calcium (Ca2+). Although the figure depicts only directly activated (ionotropic) ion channels, you should realize that many ion channels are activated indirectly, by metabotropic receptors coupled to G proteins.
The neurotransmitter-dependent sodium channel is the most important source of excitatory postsynaptic potentials. As we saw, sodium–potassium transporters keep sodium outside the cell, waiting for the forces of diffusion and electrostatic pressure to push it in. Obviously, when sodium channels are opened, the result is a depolarization—an excitatory postsynaptic potential (EPSP) . (See Figure 2.35a . ) We also saw that sodium–potassium transporters maintain a small surplus of potassium ions inside the cell. If potassium channels open, some of these cations will follow this gradient and leave the cell. Because K+ is positively charged, its efflux will hyperpolarize the membrane, producing an inhibitory postsynaptic potential (IPSP). (See Figure 2.35b . ) At many synapses, inhibitory neurotransmitters open the chloride channels, instead of (or in addition to) potassium channels. The effect of opening chloride channels depends on the membrane potential of the neuron. If the membrane is at the resting potential, nothing happens, because (as we saw earlier) the forces of diffusion and electrostatic pressure balance perfectly for the chloride ion. However, if the membrane potential has already been depolarized by the activity of excitatory synapses located nearby, then the opening of chloride channels will permit Cl− to enter the cell. The influx of anions will bring the membrane potential back to its normal resting condition. Thus, the opening of chloride channels serves to neutralize EPSPs. (See Figure 2.35c . )
FIGURE 2.35 Ionic Movements During Postsynaptic Potentials
The fourth type of neurotransmitter-dependent ion channel is the calcium channel. Calcium ions (Ca2+), being positively charged and being located in highest concentration outside the cell, act like sodium ions; that is, the opening of calcium channels depolarizes the membrane, producing EPSPs. But calcium does even more. As we saw earlier in this chapter, the entry of calcium into the terminal button triggers the migration of synaptic vesicles and the release of the neurotransmitter. In the dendrites of the postsynaptic cell, calcium binds with and activates special enzymes. These enzymes have a variety of effects, including the production of biochemical and structural changes in the postsynaptic neuron. As we will see in Chapter 13 , one of the ways in which learning affects the connections between neurons involves changes in dendritic spines initiated by the opening of calcium channels. (See Figure 2.35d . )
Termination of Postsynaptic Potentials
Postsynaptic potentials are brief depolarizations or hyperpolarizations caused by the activation of postsynaptic receptors with molecules of a neurotransmitter. They are kept brief by two mechanisms: reuptake and enzymatic deactivation.
The postsynaptic potentials produced by most neurotransmitters are terminated by reuptake . This process is simply an extremely rapid removal of neurotransmitter from the synaptic cleft by the terminal button. The neurotransmitter does not return in the vesicles that get pinched off the membrane of the terminal button. Instead, the membrane contains special transporter molecules that draw on the cell’s energy reserves to force molecules of the neurotransmitter from the synaptic cleft directly into the cytoplasm—just as sodium–potassium transporters move Na+ and K+ across the membrane. When an action potential arrives, the terminal button releases a small amount of neurotransmitter into the synaptic cleft and then takes it back, giving the postsynaptic receptors only a brief exposure to the neurotransmitter. (See Figure 2.36 . )
Enzymatic deactivation is accomplished by an enzyme that destroys molecules of the neurotransmitter. Postsynaptic potentials are terminated in this way for acetylcholine (ACh) and for neurotransmitters that consist of peptide molecules. Transmission at synapses on muscle fibers and at some synapses between neurons in the central nervous system is mediated by ACh. Postsynaptic potentials produced by ACh are short lived because the postsynaptic membrane at these synapses contains an enzyme called acetylcholinesterase (AChE) . AChE destroys ACh by cleaving it into its constituents: choline and acetate. Because neither of these substances is capable of activating postsynaptic receptors, the postsynaptic potential is terminated once the molecules of ACh are broken apart. AChE is an extremely energetic destroyer of ACh; one molecule of AChE will chop apart more that 5000 molecules of ACh each second.
FIGURE 2.36 Reuptake
Molecules of a neurotransmitter that has been released into the synaptic cleft are transported back into the terminal button.
You will recall that Kathryn, the woman featured in the case history that opened this chapter, suffered from progressive muscular weakness. As her neurologist discovered, Kathryn had myasthenia gravis. This disease was first described in 1672 by Thomas Willis, an English physician. The term literally means “grave muscle weakness.” It is not a very common disorder, but most experts believe that many mild cases go undiagnosed.
In 1934, Dr. Mary Walker remarked that the symptoms of myasthenia gravis resembled the effects of curare, a poison that blocks neural transmission at the synapses on muscles. A drug called physostigmine, which deactivates acetylcholinesterase, serves as an antidote for curare poisoning. As we just saw, AChE is an enzyme that destroys the ACh and terminates the postsynaptic potentials it produces. By deactivating AChE, physostigmine greatly increases and prolongs the effects of ACh on the postsynaptic membrane. Thus, it increases the strength of synaptic transmission at the synapses on muscles and reverses the effects of curare. ( Chapter 4 will say more about both curare and physostigmine.)
Dr. Walker reasoned that if physostigmine reversed the effects of curare poisoning, perhaps it would also reverse the symptoms of myasthenia gravis. She tried it, and it did within a matter of a few minutes. Later, pharmaceutical companies discovered drugs that could be taken orally and that produced longer-lasting effects. Nowadays, an injectable drug is used to make the diagnosis (as in Kathryn’s case), and an oral drug is used to treat it. Unfortunately, no cure has yet been found for myasthenia gravis.
Like multiple sclerosis, myasthenia gravis is an autoimmune disease. For some reason the immune system becomes sensitized against the protein that makes up acetylcholine receptors. Almost as fast as new ACh receptors are produced, the immune system destroys them.
Effects of Postsynaptic Potentials: Neural Integration
We have seen how neurons are interconnected by means of synapses, how action potentials trigger the release of neurotransmitters, and how these chemicals initiate excitatory or inhibitory postsynaptic potentials. Excitatory postsynaptic potentials increase the likelihood that the postsynaptic neuron will fire; inhibitory postsynaptic potentials decrease this likelihood. (Remember, “firing” refers to the occurrence of an action potential.) Thus, the rate at which an axon fires is determined by the relative activity of the excitatory and inhibitory synapses on the soma and dendrites of that cell. If there are no active excitatory synapses or if the activity of inhibitory synapses is particularly high, that rate could be close to zero.
Let us look at the elements of this process. To see an interactive animation of the information presented in the rest of this chapter,
The interaction of the effects of excitatory and inhibitory synapses on a particular neuron is called neural integration . (Integration means “to make whole,” in the sense of combining two or more functions.) Figure 2.37 illustrates the effects of excitatory and inhibitory synapses on a postsynaptic neuron. The top panel shows what happens when several excitatory synapses become active. The release of the neurotransmitter produces depolarizing EPSPs in the dendrites of the neuron. These EPSPs (represented in red) are then transmitted down the dendrites, across the soma, to the axon hillock located at the base of the axon. If the depolarization is still strong enough when it reaches this point, the axon will fire. (See Figure 2.37a . )
Now let’s consider what would happen if, at the same time, inhibitory synapses also become active. Inhibitory postsynaptic potentials are hyperpolarizing—they bring the membrane potential away from the threshold of excitation. Thus, they tend to cancel the effects of excitatory postsynaptic potentials. (See Figure 2.37b . )
The rate at which a neuron fires is controlled by the relative activity of the excitatory and inhibitory synapses on its dendrites and soma. If the activity of excitatory synapses goes up, the rate of firing will go up. If the activity of inhibitory synapses goes up, the rate of firing will go down.
Note that neural inhibition (that is, an inhibitory postsynaptic potential) does not always produce behavioral inhibition. For example, suppose a group of neurons inhibits a particular movement. If these neurons are inhibited, they will no longer suppress the behavior. Thus, inhibition of the inhibitory neurons makes the behavior more likely to occur. Of course, the same is true for neural excitation. Excitation of neurons that inhibit a behavior suppresses that behavior. For example, when we are dreaming, a particular set of inhibitory neurons in the brain becomes active and prevents us from getting up and acting out our dreams. (As we will see in Chapter 9 , if these neurons are damaged, people will act out their dreams.) Neurons are elements in complex circuits; without knowing the details of these circuits, one cannot predict the effects of the excitation or inhibition of one set of neurons on an organism’s behavior.
Autoreceptors
Postsynaptic receptors detect the presence of a neurotransmitter in the synaptic cleft and initiate excitatory or inhibitory postsynaptic potentials. But the postsynaptic membrane is not the only location of receptors that respond to neurotransmitters. Many neurons also possess receptors that respond to the neurotransmitter that they themselves release, called autoreceptors .
Autoreceptors can be located on the membrane of any part of the cell, but in this discussion we will consider those located on the terminal button. In most cases these autoreceptors do not control ion channels. Thus, when stimulated by a molecule of the neurotransmitter, autoreceptors do not produce changes in the membrane potential of the terminal button. Instead, they regulate internal processes, including the synthesis and release of the neurotransmitter. (As you may have guessed, autoreceptors are metabotropic; the control they exert on these processes is accomplished through G proteins and second messengers.) In most cases the effects of autoreceptor activation are inhibitory; that is, the presence of the neurotransmitter in the extracellular fluid in the vicinity of the neuron causes a decrease in the rate of synthesis or release of the neurotransmitter. Most investigators believe that autoreceptors are part of a regulatory system that controls the amount of neurotransmitter that is released. If too much is released, the autoreceptors inhibit both production and release; if not enough is released, the rates of production and release go up.
FIGURE 2.37 Neural Integration
(a) If several excitatory synapses are active at the same time, the EPSPs they produce (shown in red) summate as they travel toward the axon, and the axon fires. (b) If several inhibitory synapses are active at the same time, the IPSPs they produce (shown in blue) diminish the size of the EPSPs and prevent the axon from firing.
Other Types of Synapses
So far, the discussion of synaptic activity has referred only to the effects of postsynaptic excitation or inhibition. These effects occur at axosomatic or axodendritic synapses. Axoaxonic synapses work differently. Axoaxonic synapses do not contribute directly to neural integration. Instead, they alter the amount of neurotransmitter released by the terminal buttons of the postsynaptic axon. They can produce presynaptic modulation: presynaptic inhibition or presynaptic facilitation.
As you know, the release of a neurotransmitter by a terminal button is initiated by an action potential. Normally, a particular terminal button releases a fixed amount of neurotransmitter each time an action potential arrives. However, the release of neurotransmitter can be modulated by the activity of axoaxonic synapses. If the activity of the axoaxonic synapse decreases the release of the neurotransmitter, the effect is called presynaptic inhibition . If it increases the release, it is called presynaptic facilitation . (See Figure 2.38 . ) By the way, as we will see in Chapter 4 , the active ingredient in marijuana exerts its effects on the brain by binding with presynaptic receptors.
Many very small neurons have extremely short processes and apparently lack axons. These neurons form dendrodendritic synapses, or synapses between dendrites. Because these neurons lack long axonal processes, they do not transmit information from place to place within the brain. Most investigators believe that they perform regulatory functions, perhaps helping to organize the activity of groups of neurons. Because these neurons are so small, they are difficult to study; therefore, little is known about their function.
FIGURE 2.38 An Axoaxonic Synapse
The activity of terminal button A can increase or decrease the amount of neurotransmitter released by terminal button B.
Some larger neurons, as well, form dendrodendritic synapses. Some of these synapses are chemical, indicated by the presence of synaptic vesicles in one of the juxtaposed dendrites and a postsynaptic thickening in the membrane of the other. Other synapses are electrical; the membranes meet and almost touch, forming a gap junction . The membranes on both sides of a gap junction contain channels that permit ions to diffuse from one cell to another. Thus, changes in the membrane potential of one neuron induce changes in the membrane of the other. (See Figure 2.39 . ) Although most gap junctions in vertebrate synapses are dendrodendritic, axosomatic and axodendritic gap junctions also occur. Gap junctions are common in invertebrates; their function in the vertebrate nervous system is not known.
FIGURE 2.39 A Gap Junction
A gap junction permits direct electrical coupling between the membranes of adjacent neurons.
(From Bennett, M. V. L., and Pappas, G. D. The Journal of Neuroscience, 1983, 3, 748–761. Reprinted with permission.)
Nonsynaptic Chemical Communication
Neurotransmitters are released by terminal buttons of neurons and bind with receptors in the membrane of another cell located a very short distance away. The communication at each synapse is private. Neuromodulators are chemicals released by neurons that travel farther and are dispersed more widely than are neurotransmitters. Most neuromodulators are peptides , chains of amino acids that are linked together by chemical attachments called peptide bonds (hence their name). Neuromodulators are secreted in larger amounts and diffuse for longer distances, modulating the activity of many neurons in a particular part of the brain. For example, neuromodulators affect general behavioral states such as vigilance, fearfulness, and sensitivity to pain. Chapter 4 discusses the most important neurotransmitters and neuromodulators.
Hormones are secreted by cells of endocrine glands (from the Greek endo-, “within,” and krinein, “to secrete”) or by cells located in various organs, such as the stomach, the intestines, the kidneys, and the brain. Cells that secrete hormones release these chemicals into the extracellular fluid. The hormones are then distributed to the rest of the body through the bloodstream. Hormones affect the activity of cells (including neurons) that contain specialized receptors located either on the surface of their membrane or deep within their nuclei. Cells that contain receptors for a particular hormone are referred to as target cells for that hormone; only these cells respond to its presence. Many neurons contain hormone receptors, and hormones are able to affect behavior by stimulating the receptors and changing the activity of these neurons. For example, a sex hormone, testosterone, increases the aggressiveness of most male mammals.
FIGURE 2.40 Action of Steroid Hormones
Steroid hormones affect their target cells by means of specialized receptors in the nucleus. Once a receptor binds with a molecule of a steroid hormone, it causes genetic mechanisms to initiate protein synthesis.
Peptide hormones exert their effects on target cells by stimulating metabotropic receptors located in the membrane. The second messenger that is generated travels to the nucleus of the cell, where it initiates changes in the cell’s physiological processes. Steroid hormones consist of very small fat-soluble molecules. (Steroid derives from the Greek stereos, “solid,” and Latin oleum, “oil.” They are synthesized from cholesterol.) Examples of steroid hormones include the sex hormones secreted by the ovaries and testes and the hormones secreted by the adrenal cortex. Because steroid hormones are soluble in lipids, they pass easily through the cell membrane. They travel to the nucleus, where they attach themselves to receptors located there. The receptors, stimulated by the hormone, then direct the machinery of the cell to alter its protein production. (See Figure 2.40 . )
In the past few years, investigators have discovered the presence of steroid receptors in terminal buttons and around the postsynaptic membrane of some neurons. These steroid receptors influence synaptic transmission, and they do so rapidly. Exactly how they work is still not known.
SECTION SUMMARY: Communication Between Neurons
Synapses consist of junctions between the terminal buttons of one neuron and the membrane, another neuron, a muscle cell, or a gland cell. When an action potential is transmitted down an axon, the terminal buttons at the end release a neurotransmitter, a chemical that produces either depolarizations (EPSPs) or hyperpolarizations (IPSPs) of the postsynaptic membrane. The rate of firing of the axon of the postsynaptic neuron is determined by the relative activity of the excitatory and inhibitory synapses on the membrane of its dendrites and soma—a phenomenon known as neural integration.
Terminal buttons contain synaptic vesicles. Most terminal buttons contain two sizes of vesicles, the smaller of which are found in greatest numbers around the release zone of the presynaptic membrane. When an action potential is transmitted down an axon, the depolarization opens voltage-dependent calcium channels, which permit Ca2+ to enter. The calcium ions bind with the clusters of protein molecules in the membranes of synaptic vesicles that are docked at the release zone. The protein clusters spread apart, causing the vesicles to break open and release the neurotransmitter. Vesicles in the ready release pool briefly “kiss” the inside of the presynaptic membrane, release their contents, and then break away to be refilled. Those in the recycling pool and reserve pool completely fuse with the presynaptic membrane and lose their identity. The membrane contributed by these vesicles pinches off into the cytoplasm and is recycled in the production of new vesicles.
The activation of postsynaptic receptors by molecules of a neurotransmitter causes neurotransmitter-dependent ion channels to open, resulting in postsynaptic potentials. Ionotropic receptors contain ion channels, which are directly opened when a ligand attaches to the binding site. Metabotropic receptors are linked to G proteins, which, when activated, open ion channels—usually by producing a chemical called a second messenger.
The nature of the postsynaptic potential depends on the type of ion channel that is opened by the postsynaptic receptors at a particular synapse. Excitatory postsynaptic potentials occur when Na+ enters the cell. Inhibitory postsynaptic potentials are produced when K+ leaves the cell or Cl− enters it. The entry of Ca2+ produces EPSPs, but, even more important, it activates special enzymes that cause physiological changes in the postsynaptic cell that are involved in learning.
Postsynaptic potentials are normally very brief. They are terminated by two means. Acetylcholine is deactivated by the enzyme acetylcholinesterase, and peptides are deactivated by a variety of enzymes. Molecules of the other neurotransmitters are removed from the synaptic cleft by means of transporters located in the presynaptic membrane. This retrieval process is called reuptake.
The presynaptic membrane, as well as the postsynaptic membrane, contains receptors that detect the presence of a neurotransmitter. Presynaptic receptors, also called autoreceptors, monitor the quantity of neurotransmitter that a neuron releases and, apparently, regulate the amount that is synthesized and released.
Axosomatic and axodendritic synapses are not the only kinds found in the nervous system. Axoaxonic synapses either reduce or enhance the amount of neurotransmitter released by the postsynaptic terminal button, producing presynaptic inhibition or presynaptic facilitation. Dendrodendritic synapses also exist, but their role in neural communication is not yet understood.
Nonsynaptic chemical transmission is similar to synaptic transmission. Peptide neuromodulators and hormones activate metabotropic peptide receptors located in the membrane; their effects are mediated through the production of second messengers. Steroid hormones enter the nucleus, where they bind with receptors that are capable of altering the synthesis of proteins that regulate the cell’s physiological processes. These hormones also bind with receptors located elsewhere in the cell, but less is known about their functions.
■ THOUGHT QUESTION
· 1. Why does synaptic transmission involve the release of chemicals? Direct electrical coupling of neurons is far simpler, so why do our neurons not use it more extensively? (A tiny percentage of synaptic connections in the human brain do use electrical coupling.) Normally, nature uses the simplest means possible to a given end, so there must be some advantages to chemical transmission. What do you think they are?
· 2. Consider the control of the withdrawal reflex illustrated in Figure 2.14 . Could you design a circuit using electrical synapses that would accomplish the same tasks?
Review Questions
1.
Name and describe the parts of a neuron and explain their functions.
2.
Describe the supporting cells of the central and peripheral nervous systems and explain the blood–brain barrier.
3.
Briefly describe the role of neural communication in a simple reflex and its inhibition by brain mechanisms.
4.
Describe the measurement of the action potential and explain the dynamic equilibrium that is responsible for the membrane potential.
5.
Describe the role of ion channels in action potentials and explain the all-or-none law and the rate law.
6.
Describe the structure of synapses, the release of the neurotransmitter, and the activation of postsynaptic receptors.
7.
Describe postsynaptic potentials: the ionic movements that cause them, the processes that terminate them, and their integration.
8.
Describe the regulation of the effects of the neurotransmitters by autoreceptors, presynaptic inhibition, presynaptic facilitation, and nonsynaptic communication.
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■ NEURAL CONDUCTION AND SYNAPTIC TRANSMISSION
For the nervous system to function normally, its parts must communicate among one another. The Neural Conduction and Synaptic Transmission module of the virtual brain depicts the different parts of the nervous system, which communicate by the mechanisms described in this chapter.