CHAPTER 2
SYNAPSES
A. The Concept of the Synapse
Reflexes, or automatic muscular reactions to stimuli, were examined by
Sherrington. A sensory neuron stimulates a second neuron, which stimulates a motor
neuron, which stimulates a muscle. Reflex arc refers to the circuit connecting the sensory
neuron and the muscle response. A reflex must involve communication between neurons
if one neuron is independent from another, as Cajal had shown. As a result,
measurements of reflexes may disclose some of the unique characteristics of that
communication. Sherrington pinched one of the dog's feet while fastening a harness to a
dog above the ground. The dog raised the squeezed limb after a little pause and extended
its other legs. After making a cut that severed the spinal cord's connection to the brain,
Sherrington discovered the same reflexive actions. The flexion and extension reflexes
were obviously under the control of the spinal cord. In fact, after he detached the spinal
cord from the brain, the movements became more regular. In an entire animal, signals
that travel from the brain change the reflexes, sometimes making them stronger and other
times weaker.
After a brief wait, the dog flexed that leg when Sherrington pinched its foot. An
impulse from the skin receptor to the spinal cord had to travel up an axon at that time,
and then it had to return from the spinal cord down the leg to a muscle. Sherrington
calculated the speed at which the impulse moved to cause the reaction and assessed the
entire distance the impulse covered from the skin receptor to the spinal cord to the
muscle. He discovered that the reflex arc's conduction speed fluctuated but was never
higher than 15 meters per second (m/s). Action potential velocities along sensory or
motor nerves, however, were previously reported at roughly 40 m/s. Sherrington deduced
that a process must be slowing conduction across the reflex and that the delay takes place
at the point when one neuron connects with another.
According to Sherrington, repeated stimuli over a short period of time have an
additive impact. He called this occurrence "temporal summation," which is just summing
over time. A few quickly repeated pinches to the dog's foot instead of one mild pinch
brought on a response. Sherrington hypothesized that a single squeeze did not cause the
next neuron's excitation threshold to be reached.Presynaptic neurons are those that
transmit information, and postsynaptic neurons are those that receive it. Sherrington
suggested that although the postsynaptic neuron's subthreshold excitation degrades over
time, it can combine with a second excitation that happens immediately after it. In a
quick succession of pinches, each one builds on the effects of the previous ones until the
sum exceeds the postsynaptic neuron's threshold, resulting in an action potential.
Excitatory postsynaptic potential (EPSP), a graded depolarization, is a type of
potential. It happens as a result of sodium ions entering the neuron. The depolarization
decays quickly if an EPSP does not push the cell above its threshold. Eccles observed two
EPSPs after twice stimulating one axon. If the time between EPSPs was brief enough, the
second EPSP contributed to the remaining effects of the first one to create temporal
summation.
Sherrington also discovered that synapses had the ability to sum throughout space,
which is a trait of spatial summation. A neuron's responses to several synaptic inputs are
combined. Once more, Sherrington started with a pinch that was too weak to elicit a
reflex. This time, he simultaneously pinched two spots rather than pinching one point
twice.
The brain needs to sum up space in order to function properly. The majority of the
time, sensory information at a single synapses only has a minimal impact. However,
spatial summation can activate a neuron if it receives numerous incoming axons with
synchronized input. In most cases, spatial and temporal summation take place
simultaneously. In other words, a neuron may get information from numerous axons
quickly after another. It becomes difficult when various inputs are integrated.
Sherrington found that when she firmly pinched a dog's foot, both the flexor and
extensor muscles of that leg flexed. You can understand why this configuration would be
helpful. To stay balanced, a dog lifting one leg must extend the other legs. The dog
simultaneously relaxed the flexor muscles in the other legs and the extensor muscles in
the stimulated leg. Sherrington's justification made the following spinal cord connections
presumptive: The motor neurons associated to the flexor muscles of that leg and the
extensor muscles of the other legs are excited when the foot is pinched, thanks to a signal
that travels along a sensory neuron to an interneuron (an intermediary neuron).
Later scientists used physiological evidence to support Sherrington's hypotheses
about inhibitory synapses. The input from an axon hyperpolarizes the postsynaptic cell at
these synapses. In other words, it makes the cell more negatively charged, which pushes
it further away from the threshold and reduces the likelihood of an action potential. An
inhibitory postsynaptic potential (IPSP), also known as a transient hyperpolarization of a
membrane, resembles an EPSP. An IPSP happens when synaptic input selectively opens
the gates for chloride ions to enter the cell or for potassium ions to leave the cell (both of
which carry negative charges).
Inhibition is a concept that we take for granted today, but when Sherrington first
proposed the idea, no one could think of a method to make it happen. It was important to
establish the concept of inhibition for both neuroscience and psychology. Every time we
discuss restraining an impulse, we refer to a Sherrington-initiated idea.
While some synapses have immediate, short-lived effects, others have gradual,
protracted consequences. The combined effect of two synapses can frequently be greater
than or less than the sum of the effects of the individual synapses. Different synaptic
pairings summate with one another more powerfully than others. Even without synaptic
input, the majority of neurons produce action potentials on a regular basis. In these
situations, IPSPs decrease action potential frequency while EPSPs increase it above the
spontaneous rate. For instance, if a neuron spontaneously fires at a rate of 10 action
potentials per second, an EPSP stream may boost that rate to 15 or more, but an IPSP
predominance may reduce that rate to 5 or less.
B. Chemical Events at the Synapse
The sympathetic nervous system is responsible for stimulating the heart rate,
inducing relaxation of the stomach muscles, expanding the pupils of the eyes, and
regulating various other organs. T. In 1905, R. Elliott, a British scientist, documented that
the administration of adrenaline hormone topically on the heart, stomach, or pupils elicits
identical responses to those of the sympathetic nervous system. According to Elliott's
proposal, the activation of muscles by the sympathetic nerves occurs through the release
of adrenaline or a comparable chemical.
Loewi conducted multiple stimulations of the vagus nerve, resulting in a reduction
of the heart rate of a frog. Subsequently, the researcher procured fluid from the
pericardial sac of the aforementioned heart, and subsequently transplanted it into the
cardiac organ of another frog. The experimental results evinced a reduction in the
frequency of contractions of the second heart. Subsequently, Loewi proceeded to induce
stimulation of the accelerator nerve in the first frog's heart, resulting in a notable increase
in the heart rate. Upon extracting fluid from the aforementioned heart and subsequently
administering it to the cardiac organ of a secondary frog, an elevation in heart rate was
observed.
Two distinct nerve stimulations were observed to elicit opposing effects on heart
rate, with one nerve inducing inhibition and the other nerve inducing stimulation. The
individual was aware that they were gathering and transporting chemical substances,
rather than uncontained electrical energy. Thus, Loewi arrived at the conclusion that
nerve impulses are transmitted through the release of chemical messengers. According to
Loewi, he stated that had he conceived of this particular experiment during the daytime,
he would have likely disregarded it as impractical. The individual's daytime cognition
suggested that even if synapses were to release chemicals, the quantity of such release
would likely be negligible. Fortuitously, upon his realization that the experiment was not
expected to yield positive results, he had already executed it in its entirety, and it indeed
produced favorable outcomes. The individual was awarded a Nobel Prize.
Comprehending the chemical occurrences transpiring at a synapse is a fundamental
aspect of comprehending the nervous system. Annually, scholars uncover an increasing
amount of information regarding synapses, their configuration, and the correlation
between said configuration and their operation.
At the synaptic junction, a neuron discharges neurotransmitters that impact the
functioning of another neuron. The aforementioned substances are commonly referred to
as neurotransmitters. According to Moroz, Ctenophores, which may be considered as the
earliest and most rudimentary animals, are believed to possess solely one type of
neurotransmitter, namely glutamate. The majority of the remaining members of the
animal kingdom possess a comparable or complete set of transmitters as those found in
humans. Nitric oxide (NO), a gaseous substance discharged by numerous small local
neurons, is regarded as the most peculiar transmitter. It is important to differentiate
between nitric oxide (NO) and nitrous oxide (N2O), which is commonly referred to as
"laughing gas." Nitric oxide, when present in large amounts, can be toxic and its
production in a laboratory setting can be challenging. However, a significant number of
neurons possess an enzyme that facilitates proficient production of it. Upon stimulation,
numerous neurons release nitric oxide. Nitric oxide has the ability to dilate the adjacent
blood vessels, which results in an augmented blood supply to the respective brain region,
apart from its impact on other neurons.
Tryptophan, an amino acid that serves as the precursor to serotonin, is able to
traverse the blood-brain barrier through a specialized transport mechanism that it shares
with other amino acids of significant size. Consuming foods that are high in tryptophan,
such as soy, can lead to an increase in serotonin levels, while consuming foods that are
low in tryptophan, such as maize (American corn), can result in a decrease in serotonin
levels. Tryptophan faces competition from other large amino acids, including
phenylalanine, which are more abundant and share the same transport system. Therefore,
augmenting tryptophan intake may not be the most effective strategy for enhancing
serotonin levels. Reducing the intake of phenylalanine is a potential method for
augmenting tryptophan transportation to the brain. Another approach is to consume
carbohydrates. Carbohydrates have been found to stimulate the secretion of insulin, a
hormone that facilitates the uptake of various amino acids by body cells. This process
ultimately leads to a reduction in the competition for tryptophan within the bloodstream.
The majority of neurotransmitters are synthesized in the presynaptic terminal,
which is located in close proximity to the site of release. The storage of neurotransmitter
molecules in vesicles, which are small and nearly spherical packets, occurs at the
presynaptic terminal. Nitric oxide behaves differently from other neurotransmitters in that
it is immediately released by neurons upon formation, rather than being stored.
Additionally, the presynaptic terminal retains a significant amount of neurotransmitter
outside of the vesicles. Neurons which secrete serotonin, dopamine, or norepinephrine are
equipped with an enzyme known as monoamine oxidase (MAO), which facilitates the
breakdown of these neurotransmitters into inert chemicals, thereby impeding the
accumulation of neurotransmitters to potentially hazardous levels. MAO inhibitors were
the initial antidepressant drugs that were discovered by psychiatrists. The inhibition of
MAO leads to an elevation in the levels of serotonin, dopamine, and norepinephrine in
the brain. Nevertheless, MAO inhibitors exhibit additional effects, and the precise
mechanism by which they alleviate depression remains uncertain.
The neurotransmitter is not released by the action potential at the termination of
an axon. Depolarization triggers the activation of voltage-dependent calcium channels
located in the presynaptic terminal. Following the influx of calcium into the terminal,
exocytosis is triggered within a timeframe of 1-2 milliseconds, resulting in the discharge
of neurotransmitter from the presynaptic neuron. The release of a transmitter during an
action potential is not always successful, and the quantity of the released transmitter is
subject to variation. Following its release from the presynaptic cell, the neurotransmitter
undergoes diffusion across the synaptic cleft towards the postsynaptic membrane, where
it subsequently binds to a receptor. The diffusion of the neurotransmitter across the
synaptic cleft occurs within a time frame of 0.01 ms, and the width of the cleft is
estimated to be between 20 and 30 nm.
Sherrington's postulation regarding the synapse was straightforward, whereby the
input generated either excitation or inhibition, representing a binary mechanism. During
Eccles' experimentation with individual cells, he selectively opted for cells that generated
short-lived EPSPs and IPSPs, which were binary in nature. Initially, the revelation of
chemical transmission at synapses did not bring about any significant alteration. The
impact of a given neurotransmitter is contingent upon the specific receptor it binds to on
the postsynaptic cell. Upon binding of the neurotransmitter to its receptor, the receptor
may elicit an ionotropic effect by opening a channel, or a metabotropic effect by inducing
a slower but more sustained response.
Neurotransmitters elicit ionotropic effects at a specific receptor, which
corresponds to the transient on/off effects that were investigated by Sherrington and
Eccles. Consider a paper bag that has been closed by twisting its opening. Upon binding
of the neurotransmitter to an ionotropic receptor, the receptor undergoes a conformational
change that results in the opening of its central channel. The shape of the channel is such
that it selectively allows the passage of a specific type of ion. Transmitter-gated or
ligand-gated channels are distinct from voltage-gated sodium and potassium channels
found along an axon. A ligand refers to a chemical entity that exhibits binding affinity
towards a specific molecular target. In the context of neurotransmission, the binding of a
neurotransmitter to its corresponding receptor results in the opening of an ion channel.
The ionotropic effects manifest expeditiously, occasionally in under a millisecond
subsequent to the binding of the transmitter. The decay of effects exhibits a half-life of
approximately 5 milliseconds. The majority of excitatory ionotropic synapses in the brain
employ glutamate as their neurotransmitter.
Neurotransmitters can induce metabotropic effects at various receptors through
the initiation of a series of metabolic reactions. These effects tend to have a longer
duration compared to ionotropic effects, although they may take longer to manifest
initially. According to North, the metabotropic effects become apparent at least 30
milliseconds subsequent to the transmitter's release. Generally, the duration of these
events ranges from a few seconds to occasionally exceeding that. While ionotropic
effects are primarily mediated by glutamate or GABA, metabotropic synapses utilize a
variety of neurotransmitters such as dopamine, norepinephrine, and serotonin.
Upon binding of a neurotransmitter to a metabotropic receptor, the receptor
protein undergoes conformational changes that traverse the cell membrane. The receptor's
other end is connected to a G protein, which is a protein that is coupled to guanosine
triphosphate (GTP), a molecule that stores energy. Upon bending of the receptor protein,
the G protein becomes dissociated, thereby enabling it to translocate its energy to other
cellular locations. The outcome of the G protein is an elevation in the concentration of a
secondary messenger, namely cyclic adenosine monophosphate (cyclic AMP), within the
cellular environment. Similar to the initial messenger, which is the neurotransmitter,
conveying information to the postsynaptic cell, the second messenger transmits signals to
intracellular regions. It has the potential to either facilitate or impede the flow of ions
through the cellular membrane, or trigger a specific segment of a chromosome. It is
important to observe the distinction between ionotropic and metabotropic synapses. The
former has a limited impact on a specific area of the membrane, while the latter, through
its second messenger, modulates the activity of the entire cell for an extended duration.
Ionotropic and metabotropic synapses are implicated in distinct behavioral phenomena.
The acquisition of prompt and current information for vision and hearing is essential for
the brain, which is facilitated by ionotropic synapses.
According to Ludwig and Leng, neuropeptides are commonly classified as
neuromodulators due to their unique properties that distinguish them from other
transmitters. In contrast to the majority of neurotransmitters that are synthesized within
the presynaptic terminal, neuropeptides are synthesized within the cell body of the neuron
and subsequently transported to other regions of the cell via a slow process. In contrast to
various other neurotransmitters, neuropeptides are predominantly released via dendrites,
as well as the cell body and axonal periphery. The release of a neurotransmitter can be
initiated by a single action potential, whereas the release of neuropeptides necessitates
repetitive stimulation.
The human brain possesses a diverse array of receptor subtypes for every
neurotransmitter. The chemical structure, drug responses, and behavioral functions of
receptors for a particular transmitter exhibit variability. The variability in properties
presents an opportunity to develop pharmaceuticals with distinct impacts on behavior.
The nausea experienced by cancer patients during treatment is mediated by the serotonin
receptor type 3. The drug ondansetron is known to block this receptor, thereby alleviating
the nausea symptoms and allowing patients to undergo treatment without discomfort.
A pharmaceutical agent possessing a chemical structure similar to that of a
neurotransmitter has the capacity to bind to the corresponding receptor site. Several
hallucinogenic drugs, including lysergic acid diethylamide (LSD), possess a chemical
structure that is similar to that of serotonin. These drugs have the ability to alter
perception. They bind to serotonin type 2A (5-HT2A) receptors and induce stimulation
during inappropriate temporal intervals or for extended periods beyond the norm. The
ingestion of LSD has been observed to enhance the interconnectivity among distinct
regions of the brain that typically exhibit limited communication with each other. One
plausible hypothesis for the hallucinogenic phenomenon is that heightened spontaneous
neural activity within the brain supersedes the sensory input received from the organs of
perception.
The compound nicotine, which is found in tobacco, has the ability to activate a
group of acetylcholine receptors that are commonly referred to as nicotinic receptors. The
abundance of nicotinic receptors on dopamine-releasing neurons results in an increase in
dopamine release upon nicotine consumption, as evidenced by studies conducted by
Levin and Rose and Pontieri. Nicotine stimulation is considered rewarding due to its
association with dopamine release, which is commonly linked to the experience of
reward.
Opiate substances are either derived from the opium poppy or possess chemical
similarities to opium-derived compounds. Commonly known opioids comprise morphine,
heroin, and methadone. For centuries, individuals have utilized morphine and other
opiates without possessing knowledge regarding the drugs' impact on the brain.
Upon activation of a receptor by acetylcholine, the enzyme acetylcholinesterase
(a-SEE-til-ko-lih-NES-teh-raze) hydrolyzes it into two distinct fragments, namely acetate
and choline. Choline is observed to undergo diffusion towards the presynaptic neuron,
where it is subsequently reabsorbed and recombined with pre-existing acetate within the
neuron to reform acetylcholine. Despite the high efficiency of the recycling process, it is
time-consuming, and not all molecules released by the presynaptic neuron are
reabsorbed. According to Liu and Tsien's research in 1995, the depletion of
neurotransmitter at a synapse occurs when a rapid succession of action potentials takes
place, resulting in a slower or interrupted transmission as the presynaptic cell fails to
replenish it in time. Serotonin and catecholamines, namely dopamine, norepinephrine,
and epinephrine, do not undergo degradation into inert fragments upon reaching the
postsynaptic membrane.
The receptors are detached from by them in a straightforward manner. At this
juncture, the subsequent course of action may differ. The majority of released
neurotransmitter molecules are taken up intact by the presynaptic neuron for reuse. The
aforementioned phenomenon, commonly referred to as reuptake, takes place via
specialized transmembrane proteins known as transporters. There exists inter-individual
and inter-regional variability in the functioning of transporters. In the event that
transporters fail to uptake certain transmitter molecules, said molecules will undergo
degradation via the enzymatic activity of catechol-o-methyltransferase (COMT). The
resultant metabolites are eliminated through excretion and subsequently detected in the
bloodstream and urine.
In the event that an individual dispatches an electronic mail and subsequently
experiences apprehension regarding its successful delivery, they may proceed to
retransmit the message multiple times. To mitigate inbox clutter, it may be beneficial to
implement an automated response system acknowledging receipt of a message, such as a
pre-written message stating "Thank you for your message, it has been received." There
exist certain mechanisms within the nervous system that serve the purpose of preventing
the repetition of a particular action, as in the case of the instruction "Don't send it again."
Numerous presynaptic terminals possess receptors that are responsive to the identical
neurotransmitter that they discharge. Autoreceptors are a type of receptor that can be
activated by the neurotransmitter that has been released, resulting in the inhibition of
subsequent synthesis and release. In other words, they offer critical feedback.
At the commencement of this module, it was acquired that Sherrington's
assumption of synaptic transmission being electrical in nature was incorrect. The
statement made by the individual in question may possess a degree of accuracy. Some
synapses have been found to function electrically for specific purposes. Electrical
synapses have evolved in situations where precise synchrony between two cells is crucial
due to the fact that electrical transmission is faster than even the swiftest chemical
transmission. Electrical synapses synchronize certain cells responsible for regulating
rhythmic breathing. Simultaneously inhaling on both the left and right sides holds
significance. Additionally, numerous animal species possess electrical synapses within
their physiological framework that facilitate the synchronization of swift escape
maneuvers.
Hormonal influences bear resemblance to synaptic transmission in several
aspects, such as the shared functionality of numerous chemicals as both hormones and
neurotransmitters. A hormone is a bioactive molecule that is synthesized and secreted by
endocrine cells in a specific anatomical location, and subsequently transported via the
circulatory system to target cells in distant organs or tissues, where it exerts its
physiological effects. A neurotransmitter can be likened to a telephonic signal in that it
serves to transmit a message from the sender to the intended recipient. Hormones operate
akin to a radio station, whereby they transmit a message to any recipient that is
appropriately attuned. Neuropeptides are considered to be intermediate molecules. They
exhibit diffusion solely within the confines of a specific region of the brain, without any
discernible diffusion to other anatomical locations.
Hormones play a crucial role in facilitating the synchronization of enduring
modifications across various bodily regions. Avian species undergoing migration exhibit
hormonal changes that alter their feeding and digestive patterns, thereby facilitating the
accumulation of additional energy reserves required for the extended journey. There exist
two distinct classifications of hormones, namely protein hormones and peptide hormones,
which are comprised of amino acid chains. Proteins and peptides are distinct in terms of
their chain length, with proteins being longer and peptides being shorter. Upon binding to
membrane receptors, both protein and peptide hormones initiate the activation of a
second messenger within the cell, which is analogous to the mechanism of a metabotropic
synapse.
Similar to the way in which hormones in circulation alter brain function,
hormones produced by the brain regulate the secretion of numerous other hormones. The
pituitary gland, which is affixed to the hypothalamus comprises two distinct components,
namely the anterior pituitary and the posterior pituitary, that secrete distinct sets of
hormones. The posterior pituitary gland, which is comprised of neural tissue, may be
regarded as a continuation of the hypothalamus. The synthesis of oxytocin and
vasopressin, also known as antidiuretic hormone, occurs in the neurons located in the
hypothalamus. These hormones then travel along axons to reach the posterior pituitary.
Subsequently, the hormones are released into the bloodstream by the posterior pituitary.
The anterior pituitary, which is comprised of glandular tissue, produces six hormones.
However, their release is regulated by the hypothalamus. Releasing hormones are
secreted by the hypothalamus and subsequently transported via the bloodstream to the
anterior pituitary gland. At that location, they elicit either a stimulatory or inhibitory
effect on the secretion of additional hormones. The hypothalamus regulates the
homeostasis of specific hormones in the bloodstream by utilizing a negative feedback
mechanism. In instances where the concentration of thyroid hormone is diminished, the
hypothalamus initiates the release of TSH-releasing hormone, thereby prompting the
anterior pituitary to discharge TSH. This, in turn, triggers the thyroid gland to secrete an
increased amount of thyroid hormones.
