Neurotransmission and Chemistry

I. Background

A. Sequence of events

1. Action potential generation (see Neurophysiology)

2. Propagation of action potential along axon

3. Intra-neuron communication


II. Propagation of Action Potential

A. Active process is required

1. Current not sufficient to generate an action potential is passively conducted

2. Current leaks across the axonal membrane

††††††††††† a. Magnitude of the voltage change decays

††††††††††††††††††††††† i. Exponential decay

ii. Decay increasing distance from the site that the current was introduced

3. Leakiness of the axonal membrane prevents effective passive transmission

B. Action potential occurs without decrement along the entire length of the axon

1. Action potential propagation is not passive

2. Action potentials have conduction velocity

††††††††††† a. Occurrence time differs as a function of distance from stimulation site

C. Mechanism involves the passive spread of current

1. Current created by inward movement of Na+ associated with action potential

2. Depolarizing stimuli (see below) locally depolarize the axon

a. Open voltage-gated Na+ channels

b. Cause the influx of Na+

3. Current flows passively down the axon

a. Depolarizes adjacent areas of the axon

i. Opens Na+ channels in those areas

D. Action potential can only propagate away from the source of the depolarizing current

1. Na+ channels inactivate

2. Do not "deinactivate" until the membrane returns to resting membrane potentials

E. Process

1. Na+ channels open in response to stimulus

a. Action potential at that site

2. Depolarizing current passively flows down the axon

3. Local depolarization causes adjacent Na+ channels to open and generate an action potential

a. Upstream Na+ channels inactivate

b. K+ channels open

i. Membrane repolarizes

ii. Membrane is refractory

4. Process is repeated in neighboring segment

††††††††††† a. Impulse is propagated

F. Site of action potential in vivo

1. Axon

2. Axon hillock

a. Small part of the soma where the axon originates

3. Function of the density of Na+ and K+ channels


Fuse Example:

1. Strike a match and light the fuse, like reaching threshold

2. As a fuse burns, it ignites the combustible material just ahead

3. It burns only in one direction


III. Conductance Velocity

A. Factors affecting velocity

1. Axon diameter

††††††††††† a. Direct relationship

††††††††††††††††††††††† i. Increase diameter, increase velocity

††††††††††† b. Physiologically limiting

2. Saltatory conduction

B. Saltatory conduction

1. Myelin

††††††††††† a. Function as insulation

††††††††††††††††††††††† i. Promotes movement of current down the axon

††††††††††††††††††††††† ii. Equivalent to increasing the thickness of the axonal membrane 100 fold

††††††††††††††††††††††† iii. Reduces membrane capacitance

iv. Rate of passive spread is inversely proportionate to membrane capacitance

v. Distance that the current spreads down the inside of the axon and causes an AP is enhanced by myelin

††††††††††† b. Produced by glia

††††††††††††††††††††††† i. Schwann cells in the periphery

††††††††††††††††††††††† ii. Oligodendrocytes in the CNS

††††††††††† c. Nodes of Ranvier

††††††††††††††††††††††† i. Intermittent breaks in the myelin

††††††††††††††††††††††† ii. Site of action potential regeneration

2. Time for an action potential to occur is rate limiting

††††††††††† a. Eliminate action potentials

††††††††††† b. Impulse travels faster


IV. Events at Synapse

A. Background

1. Types of synapses

a. Electrical

††††††††††† i. Rare in adult mammalian NS

††††††††††† ii. Gap junction

iii. Current flows directly through a specialized protein moleculeóconnexon

iv. Distance between the two sides of the membrane is very small (5nM)

b. Chemical

††††††††††† i. Predominant type

2. Terminology

††††††††††† a. Neurotransmitter

i. Chemical used to communicate with the postsynaptic membrane

††††††††††† b. Active zone

i. Site of neurotransmitter release

††††††††††† c. Postsynaptic density

i. Contain neurotransmitter receptors

ii. Intercellular chemical messages converted into intracellular signal

iii. Occurs in the postsynaptic cell

††††††††††† d. Neurotransmitter receptor

i. Specialized protein molecules that bind the chemical signal

ii. Transduces chemical signal into an intracellular message

††††††††††††††††††††††† iii. Nature of response depends on receptor type

††††††††††† e. Synaptic vesicle

i. Membrane spheres containing neurotransmitter

B. Events at chemical synapse

1. Neurotransmitters are synthesized and stored in synaptic vesicles

a. Takes place in the golgi apparatus

b. Transported via secretory granules

2. Action Potential arrives at the axon terminal

a. Opens a voltage gated Ca2+ channel

3. Intracellular Ca2+ concentrations signals the neurotransmitter to be released

a. Exocytosis

i. Process by which vesicles release their contents

††††††††††† b. Vesicles fuse with the active zone

c. Not known how Ca2+ acts as the signal

4. Neurotransmitter diffuses across the synaptic cleft

a. Binds to its receptor on the postsynaptic membrane

b. Postsynaptic action depends on the nature of the receptor

††††††††††† i. Events are summed over time and space (see below)

5. Neurotransmitter inactivation

a. Information in the brain is based primarily on the frequency of the signal (#/sec)

b. The magnitude of the postsynaptic response needs to be in proportion to the presynaptic signal

i. Preserves the integrity of the message

ii. Chemical message must be controlled

c. NT must be inactivated

††††††††††† i. Degradation

††††††††††† ii. Reuptake

††††††††††† iii. Diffusion

††††††††††† iv. Bioconversion


V. Neurochemistry

A. Background

1. Neurons in the human brain communicate primarily by the release of small quantities of chemical messenger

a. Neurotransmitters

i. Interact with receptors on neuronal surfaces

ii. Alter the electrical properties of neurons

B. Information transfer occurs at synapses

1. Most synapses use chemical messages released from presynaptic axonic terminals

a. Released in response to depolarization of the terminal

b. Messages diffuse across the synaptic cleft

c. Bind with specialized receptors that span the postsynaptic membrane

d. Receptor binding of the chemical messages alters neuronal function

i. Electrical

ii. Biochemical

iii. Genetic

C. Chemical communication in the human brain depends on:

1. Nature of the presynaptically released chemical message

2. Type of postsynaptic receptor to which it binds

3. Mechanism that couples receptors to effector systems in the target cell

D. Nature of chemical messages

1. Criteria for classification as a neurotransmitter

††††††††††† a. Molecule must be synthesized and stored in the presynaptic neuron

††††††††††† b. Molecule must be released by the presynaptic neuron upon stimulation

c. Application of the neurotransmitter directly to the target cell must be shown to produce the same effects as the response produced by the release of the neurotransmitter from the presynaptic neuron

2. Few chemical substances meet these criteria

E. Classification

1. Size

a. Neuropeptides: 3-30 aa's (e.g., met-enkephalin)

b. Small molecule neurotransmitters

i. Individual amino acids (glutamate, aspartate, GABA, glycine, acetycholine)

ii. Biogenic amines (dopamine, norepinephrine, epinephrine, serotonin)

2. Neurons that use particular neurotransmitters

a. Cholinergic

b. Catecholinergic

c. Serotonergic

d. Amino acidergic

e. Other (neuropeptides, NO, etc.)

3. Many neurons release more than a single neurotransmitter

††††††††††† a. Dufferential release is base on the conditions that exist

F. Cholinergic neurons

1. Utilize acetylcholine (Ach-"vagus substance") as their neurotransmitter.

a. ACh is the neurotransmitter for:

††††††††††† i. Neuromuscular junction

††††††††††† ii. Preganglionic neurons of the sympathetic and parasympathetic PNS

††††††††††† iii. Postganglionic neuron of the parasympathetic PNS

††††††††††††††††††††††† iv. Basal forebrain and brain stem complexes

††††††††††† b. ACh is synthesized from acetyl coenzyme A and choline

i. Reaction is catalyzed by CAT-choline acetyl transferase

††††††††††† c. ACh is degraded in the synaptic cleft by acetylcholinesterase

G. Catecholaminergic neurons

1. Types

††††††††††† a. Dopamine

††††††††††† b. Norepinephrine

††††††††††† c. Epinephrine

2. Synthesized from the amino acid tyrosine

a. Each has a catechol group

3. Inactivated by reuptake

††††††††††† a. Substances that block their reuptake, prolong their activity

††††††††††††††††††††††† i. Cocaine

††††††††††††††††††††††† ii. Amphetamine

H. Serotonergic (serotonin) neurons

1. 5-hydroxytryptamine, commonly referred to as 5-HT

2. Inactivated by reuptake

3. 5-HTergic neurons appear to play a role in the brain systems that regulate mood, emotional behavior, and sleep

a. Compounds like Prosak (SSRI)

i. Block reuptake

ii. Prolong activity in the synapse

I. Diffuse neuromodulatory system

1. Catecholaminergic and serotonergic neurons

2. Modulate large numbers of neurons

a. Spread diffusely throughout the nervous system

3. Use similar effector systems (see below)

4. Commonalities

a. Cell bodies for these neurons are localized to small populations of cell in the brain stem

b. Each neuron can influence many others

i. Each axon makes a 100,000 or more synapses widely spread across the brain

††††††††††† c. Synapses are designed to release the neurotransmitter into the extracellular fluid

i. Allows the NT to spread and affect many neurons

5. Sites of dopamine action

††††††††††† a. System I

††††††††††††††††††††††† i. Cells bodies in the substantia nigra

††††††††††††††††††††††† ii. Regulates movement

††††††††††† b. System II

††††††††††††††††††††††† i. Cell bodies in the ventral tegmental area (VTA)

ii. Involved in reinforcement

6. Sites of serotonin action

††††††††††† a. Cell bodies are in the raphe nuclei

b. Involved in sleep, mood and emotional behavior

7. Sites of norepinephrine action

††††††††††† a. Cell bodies are in the locus coeruleus

b. Makes the most diffuse contacts of any neurons in the CNS

i. A single neuron can make 250,000 synaptic contacts in the cerebrum

ii. Have a second axon making another 250,000 contacts in the cerebellum

††††††††††† c. Contacts are non-specific

††††††††††††††††††††††† i. General regulation of brain activity

††††††††††††††††††††††† ii. Activity is coincident to state of CNS

8. Site of acetylcholine action

††††††††††† a. Basal forebrain

††††††††††† b. Neuromuscular junction (PNS)

J. Amino acidergic neurons

1. Types

a. Glutamate (Glu)

b. Glycine (Gly)

c. Gamma-aminobutyric acid (GABA)

2. Serve as the neurotransmitters at most CNS synapses

a. Glutamate is the primary excitatory neurotransmitter

b. GABA is the principle inhibitory neurotransmitter


VI. Transduction of Chemical Signals

A. Background

1. Chemical messengers are released from the presynaptic terminal in response to an impulse traveling down the axon

a. Impulse is a unit of information

2. Information needs to be transferred to the postsynaptic neuron

3. Process of transferring information to the postsynaptic neuron is transduction

a. Neurotransmitter binds with a specific receptor protein in the postsynaptic membrane that uniquely identifies the NT

4. A limited number of chemicals that serve as NT's

a. NT's have multiple receptors (sub-types) that bind them


(The binding of the NT by the receptor is like inserting a key into a lock; if it is the correct key, it will cause conformational changes in the protein.)


B. Two major classes of receptors

1. Ligand-Gated Ion Channels (Ionotropic)

2. G-Protein-Coupled Receptors (Metabotropic)


C. Classification based on speed of chemical synaptic transmission

1. Types

a. Fast signal transduction

b. Slow signal transduction

2. Factors affecting speed

a. Diffusion of the chemical message across the synaptic cleft and bind with the receptor

b. The time it takes for the receptor to transduce the chemical signal into a functional change in the postsynaptic neuron

3. Fast neurotransmission

a. Postsynaptic receptor is a transmitter-gated ion channel

††††††††††† i. Ion channels function much more rapidly than G-proteins

b. Rate limiting step is time of diffusion

††††††††††† i. Therefore rapid (2-5 msec)

4. Slow neurotransmission

b. Postsynaptic receptor is a G-protein-coupled receptor

††††††††††† i. Rate limiting step is time for G-proteins to elicit their effect

††††††††††† ii. 100ís of msec to days

D. Ligand-gated ion channels

1. Membrane spanning proteins that form a pore

a. Pore is closed

b. NT binds to the receptor

i. Receptor undergoes a conformational change

ii. Pores open

iii. Ions can now pass through (i.e., generate current)

2. Postsynaptic potentials

††††††††††† a. Excitatory postsynaptic potentials (EPSPs)

††††††††††††††††††††††† i. Bring the membrane potential toward threshold (depolarize)

ii. Cations in or anions out

††††††††††† b. Inhibitory postsynaptic potentials (IPSPs)

††††††††††††††††††††††† i. Move membrane potential away from threshold (hyperpolarize)

††††††††††††††††††††††† ii. Anions in or cations out

3. Effects are transient

a. EPSP's and IPSP's can be summed temporally and/or spatially

i. Effects be additive or subtractive

b. When enough EPSP's are summed:

††††††††††† i. Threshold is reached

ii. Action potential results

4. NT has a direct effect on receptor

††††††††††† a. Binding of the NT opens an ion channel

b. Causes a direct change in the membrane potential

E. G-Protein-coupled receptors

1. Process

††††††††††† a. NT is bound to a postsynaptic receptor

††††††††††† b. Receptor proteins activate small protein molecules, called G-Proteins

i. Found inside the postsynaptic neuron

††††††††††† c. G-Protein activates an "effector" molecule

2. Types of effector proteins

a. Ion channels in the membrane

b. Enzymes that synthesize second messengers

i. 2nd messengers can activate other enzymes in the cytosol

ii.Enzymatic action regulates ion channel function and alter cellular metabolism

3. Receptors linked to G-Proteins are referred to as Metabotropic Receptors

a. Can have widespread metabolic effects