PHARM DISC 2

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BasicNeuroscience6.14-13.ppt

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Contributor: Stephen M. Stahl, M.D.

Basic Neuroscience

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To review principles of chemical neurotransmission
To explain G-protein systems as targets of psychotropic drugs

Objectives*

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The Nervous System

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Nervous System

Anatomically

CNS: central nervous system
Brain
Spinal Cord

PNS – peripheral nervous system
Connects CNS to rest of the body (organ function: gut, heart, urinary bladder, muscle etc)
Includes cranial and spinal nerves

Functionally

Somatic nervous system –
processing of sensory information (conscious and unconscious)
control of striated muscles (movement)

Autonomic nervous system –
control of visceral activities including cardiovascular, digestion, temp, weight and reproduction.
Composed of sympathetic and parasympathetic

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Lobes of the cerebral cortex*

Folds allow for greater surface area which fits more cortex into a smaller space. Used as anatomical landmarks.

Gyri- ridges

Sulci- depressions or groves

Frontal lobe- prefrontal cortex: executive function (personality,planning, judgement, decision making, etc). Dorsolateral prefrontal: attention, concentration, working memory, management of retrograde memory recall and mood Orbital cortex: emotional reaction to environmental situations. Primary motor cortex (precentral gyrus): all voluntary movement. Premotor and supplementary motor areas: planning and control of movement. Broca’s area – expressive speech.

Parietal lobe- primary somatosensory cortex (postcentral gyrus): receives most direct and least processed information then sends it to secondary areas. Somatosensory association area: integration of information. Angular gyrus: visual and auditory information converge

Temporal lobe- primary auditory cortex and auditory association cortex. Visual association area. Wernicke’s area: language understanding. Emotion and memory circuitry (limbic system)

Insula- viseral/sensory area

Occipital lobe- primary visual cortex and secondary visual cortex

Neuroscience, 9-15-2009

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Cellular Level

Neurons
Electrically and chemically excitable
Dendrite, cell body, axon

Glia
Astrocytes: structure, scaffolding, BBB, phagocytosis, removal of excess NT and toxin
Oligodendrocytes: myelin
Microglia: phagocytosis, release cytokines (immune response), response to damage

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Neurotransmission

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dendrites

dendritic spines

cell body (soma)

axon

en passant

presynaptic

axon terminals

presynaptic

axon terminals

General Structure of the Neuron*

1-1A

• Anatomically, neurons are set up in a wiring network to deliver information to each other through synapses in mostly a one direction network (anterograde- axon of first neuron to dendrite, soma, or axon of second neuron)

• Synapses can occur on many places of the neuron (i.e., dendrites, soma)

• All neurons have a cell body (Soma) and it receives information from other neurons through dendrites

• While the anatomical system fosters neurotransmission, it’s the chemical messengers who play a critical role in the process

• Electrical impulses convert to chemical signals (i.e., excitation-secretion coupling) at the synapses in this process; however, the chemical messengers can convert back to an electrical impulse or trigger a cascade of more chemical messengers as the transmission process unfolds

• Technically communication can travel in more than one direction and/or outside of the synapses (i.e., retrograde neurotransmission, volume neurotransmission, diffusion)

• Signal transduction cascades have two primary targets: phosphoproteins and genes.

• Phosphoproteins are a latter part of the messaging cascade and assist with gene expression through enzyme systems

• It is these gene expressions that can modify behavior but behavior can also modify genes through socio-environmental regulation of proteins which affect gene expression

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Another General Structure of the Neuron

dendritic spines

dendrites

cell body (soma)

axon

dendritic

tree

1-1B

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Classical synaptic
Retrograde
Volume (nonsynaptic) neurotransmission

Three Types of Neurotransmission*

Synaptic transmission: rapid and point-to-point, transmission from presynaptic terminal to postsynaptic cell
Retrograde signaling: involves activity-dependent release of a substance from the postsynaptic cell which then affects release of transmitter from the presynaptic terminal
Volume transmission is slower, involves release of neurotransmitter at a distance from its target sites which are extrasynaptic

receptors

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Classical Synaptic Neurotransmission*

reception

Integration/chemical

encoding

electrical encoding

signal propagation

signal transduction

3-1

neurotransmitter

light

hormone

drug

nerve impulse

neurotransmitter

Synaptic transmission involves release of a neurotransmitter from the presynaptic nerve ending and its binding to a postsynaptic receptor to produce a change in function (excitation or inhibition) in the postsynaptic neuron. Remember, though communication within a neuron can be electrical, communication between neurons is chemical.

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3-3

Classical Neurotransmission Versus Retrograde Neurotransmission

classical

retrograde

CB1 receptor

cGMP

targets

NGF

(nerve growth

factor)

NGF

(nitric oxide)

In retrograde transmission: The Neurotransmitter is released from the postsynaptic cell and binds to receptors on the terminal of the presynaptic neuron

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3-4

Classical Neurotransmission Versus Volume Neurotransmission*

In volume neurotransmission: There is no tight junction between presynaptic terminal and postsynaptic cell—it occurs without a synapse.. Release is at sites distant to the target cell. Receptors are extrasynaptic

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3-5

Volume Neurotransmission*

DA neuron

D1 receptors

synaptic neurotransmission at 1 and diffusion to 2 and 3

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G-protein linked neurotransmission
Ion-channel linked neurotransmission
Hormones
Neurotrophins

Four Types of Signalling*

As we begin discussing signal transduction, make sure to check out the video under Optional resources in the course section to help you understand.

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3-11

cell nucleus

First Messenger

membrane

Second Messenger

Third Messenger

Fourth Messenger/

Gene Expression

Four Types
of Signalling*

Ca++

ion channel linked

neurotrans-

mitter

CaMK

G-protein linked

neurotrans-mitter

CREB

P04

hormone

nuclear

receptor

complex

HRE

neurotrophin

Ras/

Raf/

MEK

ERK/RSK/

MAPK/

GSK3

genes

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Activating a Third Messenger Kinase through Cyclic AMP*

3-17

first messenger -

neurotransmitter

second messenger

inactive

protein kinase

activation

third messenger-

active

protein kinase

This picture can be found on page 14 in your book and shows the activation of a thris messenger protein kinase. Prior to this- remember, there are four elements of the G-protein linked second messenger system. Can you name them? I’ll start you off—one of the elements is the G protein. Also, before this stage, the first messenger has already changed the receptor so it can bind to the G protein; and the G protein has changed it’s shape so it can then bind to an enzyme that will be able to synthesize that second messenger.

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3-18

Activating a Third Messenger Phosphatase

through Calcium

first messenger -

neurotransmitter

second messenger

Ca++

inactive

calcineurin

third messenger -

active calcineurin

(phosphatase)

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regulatory enzymes

3-19

Third Messenger Kinases put Phosphates on Critical Proteins*

third messenger-

kinase

voltage-gated ion channel

Ligand- gated ion channel

first messenger

second messenger

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regulatory enzymes

voltage-gated ion channel

ligand- gated ion channel

third messenger -

active calcineurin

(phosphatase)

3-20

Third Messenger Phosphatases Undo what Kinases Create - Take Phosphates Off Critical Proteins*

first messenger -

neurotransmitter

second messenger

Ca++

inactive

calcineurin

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first messenger

second messenger

inactive

protein kinase

activation

third messenger-

active

protein kinase

3-30

inactive TF

activated “early” TF

FOS -

fifth messenger

Signal Transduction
Leading to
Gene Expression*

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Epigenetics*

Please read the Stahl article for further explanation