Section 2: Signal Transmission Between the Neurons

Section 2:

Signal Transmission Between the Neurons

Neurotransmission

1.Chemical synapse (Classical Synapse)

– Predominates in the vertebrate nervous system

2.Non-synaptic chemical transmission

3.Electrical synapse

– Via specialized gap junctions

– Does occur, but rare in vertebrate NS

– Astrocytes can communicate via gap junctions

Chemical Synapse

• Terminal bouton is separated from postsynaptic cell by synaptic cleft.

• Vesicles fuse with axon membrane and NT released by exocytosis.

• Amount of NTs released depends upon frequency of AP.

Non-synaptic chemical transmission

The postganglionic neurons innervate the smooth muscles.

No recognizable endplates or other postsynaptic specializations;

The multiple branches are beaded with enlargements (varicosities) that are not covered by Schwann cells and contain synaptic vesicles;

Fig. : Ending of postganglionic autonomic neurons on smooth muscle

In noradrenergic neurons, the varicosities are about 5m, with up to 20,000 varicosities per neuron;

Transmitter is apparently released at each varicosity, at many locations along each axon;

One neuron innervate many effector cells.

Fig. : Ending of postganglionic autonomic neurons on smooth muscle

Non-synaptic chemical transmission continued

Electrical Synapse• Impulses can be regenerated

without interruption in adjacent cells.

• Gap junctions:– Adjacent cells electrically

coupled through a channel.

– Each gap junction is composed of 12 connexin proteins.

• Examples:– Smooth and cardiac

muscles, brain, and glial cells.

•Electric current flow- communication takes place by flow of electric current directly from one neuron to the other

•No synaptic cleft or vesicles cell membranes in direct contact

•Communication not polarized- electric current can flow between cells in either direction

Electrical Synapses

Electrical Synapse Chemical SynapsePurves, 2001

I The Chemical Synapse and Signal Transmission

• The chemical synapse is a specialized junction that transfers nerve impulse information from a pre synaptic membrane to a postsynaptic membrane using neurotransmitters and enzymes

Synaptic connections

• ~100,000,000,000 neurons in human brain

• Each neuron contacts ~1000 cells

• Forms ~10,000 connections/cell

• How many synapses?

•Neurotransmitter- communication via a chemical intermediary called a neurotransmitter, released from one neuron and influences another

•Synaptic cleft- a small gap between the sending (presynaptic) and the receiving (postsynaptic) site

Chemical Synapses

•Synaptic vesicles- small spherical or oval organelles contain chemical transmitter used in transmission

•Polarization- communication occurs in only one direction, from sending presynaptic site, to receiving postsynaptic site

Chemical Synapses

• Precursor transport

• NT synthesis

• Storage

• Release

• Activation

• Termination ~diffusion, degradation, uptake, autoreceptors

1. Synaptic Transmission Model

PresynapticAxon Terminal

PostsynapticMembrane

Terminal Button Dendritic

Spine

(1) Precursor Transport

_ _ _

NT

(2) Synthesis

enzymes/cofactors

(3) Storage

in vesicles

Synapse

Vesicles

NT


Spine

Synapse


Spine

(4) Release

Receptors

Synapse


Spine

AP

Ca2+

Exocytosis

Each vesicle contains one quanta of neurotransmitter (approximately 5000 molecules) – quanta release

(5) Activation

(6) Termination

(6.1) Termination by... Diffusion

(6.2) Termination by...Enzymatic degradation

(6.3) Termination by... Reuptake

(6.4) Termination by... Autoreceptors

A

Autoreceptors

• On presynaptic terminal

• Binds NT

same as postsynaptic receptors

different receptor subtype

• Decreases NT release & synthesis

• Metabotropic receptors

Synaptic Transmission

• AP travels down axon to bouton.• VG Ca2+ channels open.

– Ca2+ enters bouton down concentration gradient.

– Inward diffusion triggers rapid fusion of synaptic vesicles and release of NTs.

• Ca2+ activates calmodulin, which activates protein kinase.

• Protein kinase phosphorylates synapsins.– Synapsins aid in the fusion of synaptic vesicles.

Synaptic Transmission (continued)

• NTs are released and diffuse across synaptic cleft.

• NT (ligand) binds to specific receptor proteins in postsynaptic cell membrane.

• Chemically-regulated gated ion channels open.– EPSP: depolarization.– IPSP: hyperpolarization.

• Neurotransmitter inactivated to end transmission.

2 EPSP and IPSP

(1)Excitatory postsynaptic potential (E

PSP)An AP arriving in the presynaptic terminal cause the release of neurotransmitter;The molecules bind and active receptor on the postsynaptic membrane;

(1)Excitatory postsynaptic

potential (EPSP)Opening transmitter-gated ions channels ( Na+) in postsynapticmembrane;Both an electrical and a concentration gradient driving Na+ into the cell; The postsynaptic membrane will become depolarized(EPSP).

EPSP• No threshold.• Decreases resting

membrane potential.– Closer to threshold.

• Graded in magnitude.

• Have no refractory period.

• Can summate.

(2) Inhibitory postsynaptic potential (IPSP)

• A impulse arriving in the presynaptic terminal causes the release of neurotransmitter;

•The molecular bind and active receptors on the postsynaptic membrane open CI- or, sometimes K+ channels;

• More CI- enters, K+ outer the cell, producing a hyperpolarization in the postsynaptic membrane.

•(IPSPs):–No threshold.

–Hyperpolarize postsynaptic membrane.

–Increase membrane potential.

–Can summate.

–No refractory period.

3 Synaptic Inhibition

• Presynaptic inhibition:– Amount of

excitatory NT released is decreased by effects of second neuron, whose axon makes synapses with first neuron’s axon.

• Postsynaptic inhibition

Concept: effect of inhibitory synapses on

the postsynaptic membrane. Mechanism: IPSP, inhibitory interneuron Types:

Afferent collateral inhibition( reciprocal

inhibition)

Recurrent inhibition.

(1) Postsynaptic inhibition

1) Reciprocal inhibition

Activity in the afferent fibers from the muscle spindles (stretch receptors) excites (EPSPs) directly the motor neurons supplying the muscle from which the impulses come.

Postsynaptic inhibition

At the same time, inhibits (ISPSs) those motor neurons supplying its antagonistic muscles.

1) Reciprocal inhibition

The latter response is mediated by branches of the afferent fibers that end on the interneurons.


The interneurons, in turn, secrete the inhibitory transmitter (IPSP) at synapses on the proximal dendrites or cell bodies of the motor neurons that supply the antagonist.

Neurons may also inhibit

themselves in a negative feedback

fashion.

Each spinal motor neuron regularly

gives off a recurrent collateral that

synapses with an inhibitory

interneuron which terminates on

the cell body of the spinal neuron

and other spinal motor neurons.

The inhibitory interneuron to

secrete inhibitory mediator, slows

and stops the discharge of the

motor neuron.

2) Recurrent inhibition


Concept: the inhibition occurs at the

presynaptic terminals before the s

ignal ever reaches the synapse.

The basic structure: an axon-axon s

ynapse (presynaptic synapse), A a

nd B.

Neuron A has no direct effect on neu

ron C, but it exert a Presynaptic ef

fect on ability of B to Influence C.

The presynatic effect May decrease t

he amount of neurotransmitter re

leased from B (Presynaptic inhibiti

on) or increase it (presynaptic faci

litation).

(2) Presynaptic inhibition

AAB

C

A

C

B

The mechanisms:

• Activation of the presynaptic receptors increases CI- conductance,

to decrease the size of the AP reaching the excitatory ending,

reduces Ca2+ entry and consequently the amount of excitatory transmitter decreased.

Presynaptic inhibition

• Voltage-gated K+ channels are also opened, and the resulting K+ efflux also decreases the Ca2+ influx.

Excitatory Synapse

• A active

• B more likely to fire

• Add a 3d neuron ~

A B+

Presynaptic Inhibition

Excitatory Synapse

• Axon-axon synapse

• C is inhibitory ~

A B+


C

-

Excitatory Synapse

A B+


C

-

• C active

• less NT from A when active

• B less likely to fire ~

4 Synaptic Facilitation: Presynaptic and Postsynaptic

Excitatory Synapse

• A active

• B more likely to fire ~

A B+

(1) Presynaptic Facilitation

Excitatory Synapse

A B+

Presynaptic Facilitation

C

+

• C active (excitatory)• more NT from A when

active (Mechanism:AP of A is prolonged and Ca 2+ channels are open for a longer period.)

• B more likely to fire ~

(2) Postsynaptic facilitation: neuron that has been partially depolarized is more likely to undergo AP.

-65mv

- 70mv AT REST

Vm

Time

EPSP

+

-

• Depolarization

more likely to fire ~

Record here

+

5 Synaptic Integration

• EPSPs can summate, producing AP.– Spatial summation:

• Numerous PSP converge on a single postsynaptic neuron (distance).

– Temporal summation: • Successive waves of

neurotransmitter release (time).

(1) Spatial Summation

• The accumulation of neurotransmitter in the synapse due the combined activity of several presynaptic neurons entering the Area (Space) of a Convergent Synapse.

• A space (spatial) dependent process.

-65mv

- 70mv AT REST

vm

Time

+

-

SpatialSummation +

• Multiple synapses

+

(2) Temporal Summation

• The accumulation of neurotransmitters in a synapse due to the rapid activity of a presynaptic neuron over a given Time period.

• Occurs in a Divergent Synapse. (explain later)

• Is a Time (Temporal) dependent process.

-65mv

- 70mv AT REST

Vm

Time

+

-

TemporalSummation

+

Repeated stimulation same synapse ~

(3) EPSPs & IPSPs summate

• CANCEL EACH OTHER

• Net stimulation – EPSPs + IPSPs = net effects ~

- 70mv

+

-

-

EPSP

IPSP

+

6. Divergent and Convergent Synapse

Divergent Synapse

•A junction that occurs between a presynaptic neuron and two or more postsynaptic neurons (ratio of pre to post is less than one).

•The stimulation of the postsynaptic neurons depends on temporal summation).

Convergent Synapse

Presynaptic neurons

Postsynaptic neuron

•A junction between two or more presynaptic neurons with a postsynaptic neuron (the ratio of pre to post is greater than one).

•The stimulation of the postsynaptic neuron depends on the Spatial Summation.

II Neurotransmitters and receptors

1. Basic Concepts of NT and receptor

Neurotransmitter: Endogenous signaling molecules that alter the behaviour of neurons or effector cells.

Neuroreceptor: Proteins on the cell membrane or in the cytoplasm that could bind with specific neurotransmitters and alter the behavior of neurons of effector cells

•Vast array of molecules serve as neurotransmitters

•The properties of the transmitter do not determine its effects on the postsynaptic cells

•The properties of the receptor determine whether a transmitter is excitatory or inhibitory

A neurotransmitter must (classical definition)

• Be synthesized and released from neurons• Be found at the presynaptic terminal• Have same effect on target cell when applied externally• Be blocked by same drugs that block synaptic transmission• Be removed in a specific way

Purves, 2001

Classical Transmitters (small-molecule transmitters)•Biogenic Amines

•Acetylcholine

•Catecholamines

•Dopamine

•Norepinerphrine

•Epinephrine

•Serotonin

•Amino Acids

•Glutamate

•GABA (-amino butyric acid)

•Glycine

•Neuropeptides

•Neurotrophins

•Gaseous messengers

–Nitric oxide

–Carbon Monoxide

•D-serine

Non-classical Transmitters

Agonist

A substance that mimics a specific neurotransmitter,

is able to attach to that neurotransmitter's receptor

and thereby produces the same action that the neurotransmitter usually produces.

Drugs are often designed as receptor agonists to treat a variety of diseases and disorders when the original chemical substance is missing or depleted.

Antagonist

Drugs that bind to but do not activate neuroreceptors,

thereby blocking the actions of neurotransmitters or the neuroreceptor agonists.

Receptor BReceptor A

• Same NT can bind to different -R

• different part of NT ~

NT

NT

Specificity of drugs

Drug ADrug B

Receptor BReceptor A

Five key steps in neurotransmission

• Synthesis

• Storage

• Release

• Receptor Binding

• Inactivation

Purves, 2001

Synaptic vesicles

• Concentrate and protect transmitter

• Can be docked at active zone

• Differ for classical transmitters (small, clear-core) vs. neuropeptides (large, dense-core)

Neurotransmitter Co-existence (Dale principle)Some neurons in both the PNS and CNS produce both a classical neurotransmitter (ACh or a catecholamine) and a polypeptide neurotransmitter.

They are contained in different synaptic vesicles that can be distinguished using the electron microscope.

The neuron can thus release either the classical neurotransmitter or the polypeptide neurotransmitter under different conditions.

Purves, 2001

Receptors determine whether:• Synapse is excitatory or inhibitory

– NE is excitatory at some synapses, inhibitory at others

• Transmitter binding activates ion channel directly or indirectly.– Directly

• ionotropic receptors• fast

– Indirectly• metabotropic receptors• G-protein coupled• slow

2. Receptor Activation

• Ionotropic channel– directly controls channel– fast

• Metabotropic channel– second messenger systems– receptor indirectly controls channel ~

(1) Ionotropic ChannelsneurotransmitterNTChannel

Ionotropic Channels

NT

Pore

Ionotropic Channels

NT

Ionotropic Channels

NT

(2) Metabotropic Channels

• Receptor separate from channel

• G proteins

• 2d messenger system– cAMP– other types

• Effects– Control channel– Alter properties of receptors– regulation of gene expression ~

(2.1) G protein: direct control

• NT is 1st messenger

• G protein binds to channel– opens or closes– relatively fast ~

G protein: direct control

RG

GDP

G protein: direct control

RG

GTP

Pore

(2.2) G protein: Protein Phosphorylation

Receptor

trans-ducer

primaryeffector

external signal: nt

2d messenger

secondary effector

Receptor

trans-ducer

primaryeffector

external signal: NT

2d messenger

secondary effector

GS

norepinephrine

cAMP

protein kinase

adrenergic -R

adenylylcyclase

G protein: Protein Phosphorylation

RG

GDP

AC

PK


R

AC

PK

G

GTPATP

cAMP


R

AC

PK

G

GTPATP

cAMP

P

Pore

(3) Transmitter Inactivation

• Reuptake by presynaptic terminal

• Uptake by glial cells

• Enzymatic degradation

• Presynaptic receptor

• Diffusion

• Combination of above

Summary of Synaptic

Transmission

Purves,2001

Basic Neurochemistry

3. Some Important Transmitters

(1) Acetylcholine (ACh) as NT

Acetylcholine Synthesis

choline + acetyl CoA ACh + CoA

cholineacetyltransferase

Acetylcholinesterase (AChE)

• Enzyme that inactivates ACh.

– Present on postsynaptic membrane or immediately outside the membrane.

• Prevents continued stimulation.

The Life Cycle of Ach

Ach - Distribution

• Peripheral N.S.• Excites somatic skeletal muscle (neuro-muscular jun

ction)• Autonomic NS

Ganglia

Parasympathetic NS--- Neuroeffector junction

Few sympathetic NS – Neuroeffector junction

• Central N.S. - widespreadHippocampus

Hypothalamus ~

•ACh is both an excitatory and inhibitory NT, depending on organ involved.

–Causes the opening of chemical gated ion channels.

•Nicotinic ACh receptors:

–Found in autonomic ganglia (N1) and skeletal muscle fibers (N2).

•Muscarinic ACh receptors:

–Found in the plasma membrane of smooth and cardiac muscle cells, and in cells of particular glands .

Ach Receptors

Acetylcholine Neurotransmission

• “Nicotinic” subtype Receptor:– Membrane Channel for Na+ and K+

– Opens on ligand binding– Depolarization of target (neuron, muscle)– Stimulated by Nicotine, etc.– Blocked by Curare, etc.– Motor endplate (somatic) (N2), – all autonomic ganglia, hormone

producing cells of adrenal medulla (N1)


• “Muscarinic” subtype Receptor: M1

– Use of signal transduction system

• Phospholipase C, IP3, DAG, cytosolic Ca++

– Effect on target: cell specific (heart , smooth muscle intestine )

– Blocked by Atropine, etc.– All parasympathetic target organs– Some sympathetic targets (endocrine sweat glan

ds, skeletal muscle blood vessels - dilation)


• “Muscarinic” subtype: M2

– Use of signal transduction system• via G-proteins, opens K+ channels, decrease

in cAMP levels– Effect on target: cell specific– CNS – Stimulated by ?– Blocked by Atropine, etc.

Cholinergic Agonists

• Direct– Muscarine – Nicotine

• Indirect– AChE Inhibitors ~

Cholinergic Antagonists

• Direct

Nicotinic - Curare

Muscarinic - Atropine

Ligand-Operated ACh Channels

N Receptor

G Protein-Operated ACh ChannelM receptor

(2) Monoamines as NT

Monoamines

• Catecholamines –

Dopamine - DA

Norepinephrine - NE

Epinephrine - E

• Indolamines - Serotonin - 5-HT

Mechanism of Action ( receptor)

Epi1

G protein

PLC IP3

Ca+2

Norepinephrine (NE) as NT

• NT in both PNS and CNS.

• PNS: – Smooth muscles, cardiac muscle and glands.

• Increase in blood pressure, constriction of arteries.

• CNS:– General behavior.

Adrenergic Neurotransmission

1 Receptor– Stimulated by NE, E, – blood vessels of skin, mucosa, abdominal

viscera, kidneys, salivary glands – vasoconstriction, sphincter constriction, pupil

dilation

Adrenergic Neurotransmission2 Receptor

– stimulated by, NE, E, …..– Membrane of adrenergic axon terminals (pre-sy

naptic receptors), platelets– inhibition of NE release (autoreceptor), – promotes blood clotting, pancreas decreased ins

ulin secretion


• 1 receptor– stimulated by E, ….– Mainly heart muscle cells, – increased heart rate and strength


• 2 receptor– stimulated by E ..– Lungs, most other sympathetic organs, blood

vessels serving the heart (coronary vessels),– dilation of bronchioles & blood vessels

(coronary vessels), relaxation of smooth muscle in GI tract and pregnant uterus


• 3 receptor– stimulated by E, …. – Adipose tissue, – stimulation of lipolysis

(3) Amino Acids as NT

• Glutamate acid and aspartate acid:– Excitatory Amino Acid (EAA)

• gamma-amino-butyric acid (GABA) and glycine:– Inhibitory AA

(4) Polypeptides as NT

• CCK:– Promote satiety following meals.

• Substance P:– Major NT in sensations of pain.

(5) Monoxide Gas: NO and CO

• Nitric Oxide (NO)– Exerts its effects by stimulation of cGMP.– Involved in memory and learning. – Smooth muscle relaxation.

• Carbon monoxide (CO):– Stimulate production of cGMP within neurons.– Promotes odor adaptation in olfactory neurons.– May be involved in neuroendocrine regulation in

hypothalamus.

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Section 2: Signal Transmission Between the Neurons