Chapter 30Chapter 30

General Principles of the Neuron Activities

ContentsContents

NeurotransmissionNeurotransmitter and ReceptorSynaptic PlasticityProperties of the Synaptic

Neurotransmission

NEUROTRANSMISSIONNEUROTRANSMISSIONPart I

I Synapse

1.Chemical synapse (Classical Synapse)– Predominates in the vertebrate nervous system2.Non-synaptic chemical transmission3.Electrical synapse– Via specialized gap junctions– Does occur, but rare in vertebrate NS– Astrocytes can communicate via gap junctions

1. 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.

2. Non-synaptic chemical transmission• Sympathetic Nerve

• 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 released at each varicosity

• One neuron innervate many effector cells.

Fig. : Ending of postganglionic autonomic neurons on smooth muscle

Non-synaptic chemical transmission continued

Innervation of Adrenal MedullaInnervation of Adrenal Medulla

3. 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.

1. Communication takes place by flow of electric current directly from one neuron to the other

2. No synaptic cleft or vesicles cell membranes in direct contact

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

Electrical Synapses

Electrical Synapse Chemical SynapsePurves, 2001

II The Chemical Synapse and Signal Transmission

II The Chemical Synapse and Signal II The Chemical Synapse and Signal TransmissionTransmission

The chemical synapse – 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

• How many synapses?

• Neurotransmitter- chemical intermediary 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

Terminal Button Dendritic

Spine

Synapse

Terminal Button Dendritic

Spine

(4) Release

Receptors

Synapse

Terminal Button Dendritic

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 receptorsdifferent receptor subtype

• Decreases NT release & synthesis • Metabotropic receptors

Synaptic Transmission

• AP travels down axon to bouton.• Voltage Gated 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 (突触蛋白） .

– 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 IPSP2 EPSP and IPSP

EPSP: Excitatory postsynaptic potential

IPSP: Inhibitory postsynaptic potential

EPSPEPSP

An AP arriving in the presynaptic terminal cause the release of neurotransmitter

The molecules bind and activate receptor on the postsynaptic membrane

EPSPEPSP

Opening transmitter-gated ions channels ( Na+) in postsynaptic- membrane

Both an electrical and a concentration gradient driving Na+ into the cell

The postsynaptic membrane will become depolarized (EPSP).

EPSPEPSP• No threshold.• Decreases resting

membrane potential.– Closer to threshold.

• Graded in magnitude.• Have no refractory

period.• Can summate.

IPSPIPSP 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, K+ channels

CI- influx or K+ outflux produce 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

• Postsynaptic inhibition

A

B

Concept: effect of inhibitory synapses on the postsynaptic

membrane. Mechanism:

IPSP inhibitory interneuron

Types: Afferent collateral (reciprocal) inhibition)Recurrent inhibition.

(1) Postsynaptic inhibition

Postsynaptic inhibition

Reciprocal inhibitionReciprocal inhibition

Postsynaptic inhibition

2) Recurrent inhibition2) Recurrent inhibition

• Concept: the inhibition occurs at the presynaptic terminals before the signal ever reaches the synapse.

• The basic structure: an axon-axon synapse (presynaptic synapse) between A and B.

• Neuron A has no direct effect on neuron C, but it exert a presynaptic effect on ability of B to Influence C. • decrease the amount of neuro-

transmitter released from B (Presynaptic inhibition)

(2) Presynaptic inhibition

AAB

C

A

C

B

• Activation of the presynaptic receptors increases CI- conductance EPSP

to decrease the size of the AP reaching the excitatory ending

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

Mechanisms Presynaptic inhibition

Excitatory Synapse

• A active• B more likely to fire • Add a 3d neuron ~

A B+

Presynaptic Inhibition

Excitatory Synapse

• Axon-axon synapse• C is excitatory ~

A B+

Presynaptic Inhibition

C

+

Excitatory Synapse

A B+

Presynaptic Inhibition

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

+

-

• Depolarizationmore likely to fire ~

Record here

+

5 Synaptic Integration

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

summation

(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.

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

Convergent Synapse

• A junction between two or more presynaptic neurons with a postsynaptic neuron

• The stimulation of the postsynaptic neuron depends on the spatial summation.

Part II Neurotransmitters and receptors

1. Basic Concepts• Neurotransmitter

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

• Neuroreceptor:

• Proteins on the cell membrane or in the cytoplasm

• Could bind with specific neurotransmitters

• Alter the behavior of effector cells

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 ( 胺 )

•Acetylcholine•Catecholamines

•Dopamine•Norepinerphrine•Epinephrine

•Serotonin (5-HT)•Amino Acids

•Glutamate•GABA (-amino butyric acid)•Glycine

•Neuropeptides

•Neurotrophins

•Gaseous messengers–Nitric oxide

–Carbon Monoxide

–Hydrogen sulfide

Non-classical Transmitters

71

Classes of CNS TransmittersNeurotransmitter % of

Synapses

BrainConcentrati

on

Function Primary Receptor

ClassMonoaminesCatecholamines: DA, NE, EPIIndoleamines: serotonin (5-HT)

2-5 nmol/mg protein(low)

Slow change in excitability (secs)

GPCRs

Acetylcholine (ACh) 5-10 nmol/mg protein(low)

Slow change in excitability (secs)

GPCRs

Amino acidsInhibitory: GABA, glycine

Excitatory: Glutamate, aspartate

15-20

75-80

μmol/mg protein(high)

μmol/mg protein(high)

Rapid inhibition (msecs)

Rapid excitation (msecs)

Ion channels

Ion channels

AgonistAgonistA substance that mimics a specific

neurotransmitter– able to attach to that neurotransmitter's receptor

– produces the same action as the neurotransmitter.

Drugs are often designed as receptor agonists – to treat a variety of diseases and disorders

when the original chemical substance is missing or depleted.

AntagonistAntagonist

Drugs bind to but do not activate neuroreceptors – 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

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 Neurotransmitter Co-existence

Some neurons produce both a classical neurotransmitter and a polypeptide neurotransmitter.– contained in different synaptic vesicles

– be distinguished using the electron microscope.

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

Purves, 2001

Peptide Small Molecule

Site of Co-localization

NYP NE Neurons of the locus ceruleus （蓝斑核） ; sympathetic postganglionic neurons

Dynorphin（强啡肽） ; substance P; enkephalin (脑啡肽）

GABA Striatal （纹状体） GABAergic projection neurons

VIP ACh Parasympathetic postganglionic neurons

CGRP ACh Spinal motor neurons

Neurotension（神经降压素） ; CCK

DA Neurons of the substantia nigra （黑质）

Examples of Co-localized Neuropeptides Examples of Co-localized Neuropeptides and Small Molecule Neurotransmittersand Small Molecule Neurotransmitters

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 receptor– directly controls channel– fast

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

(1) Ionotropic ReceptorneurotransmitterNTChannel

Ionotropic Receptor

NT

Pore

Ionotropic Receptor

NT

Ionotropic Receptor

NT

(2) Metabotropic Receptor• 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

Receptortrans-ducer

primaryeffector

external signal: nt

2d messenger

secondary effector

Receptortrans-ducer

primaryeffector

external signal: NT

2d messenger

secondary effector

GS

norepinephrine

cAMP

protein kinase

adrenergic -Radenylylcyclase

G protein: Protein Phosphorylation

RG

GDP

AC

PK

G protein: Protein Phosphorylation

RAC

PK

G

GTPATP

cAMP

G protein: Protein Phosphorylation

RAC

PK

G

GTPATP

cAMP

P

Pore

SOME IMPORTANT SOME IMPORTANT TRANSMITTERS AND THE TRANSMITTERS AND THE CORRESPONDING CORRESPONDING RECEPTORSRECEPTORS

3

95

Major Neurotransmitter Receptors in the CNS

Neurotransmitter Receptor Subtypes G Protein-Coupled (G) vs. Ligand-Gated Ion Channel (LG)

DA D1

D2

D3

D4

D5

GGGGG

NE/EPI α1

α2

β1

β2

β3

GGGGG

5-HT 5-HT1A

5-HT1B

5-HT1D

5-HT2A

5-HT2B

5-HT2C

5-HT3

5-HT4

GGGGGG

LGG

96

Major Neurotransmitter Receptors in the CNS

Neurotransmitter Receptor Subtypes

G Protein-Coupled (G) vs. Ligand-Gated Ion Channel

(LG)ACh Muscarinic M1

Muscarinic M2

Muscarinic M3

Muscarinic M4

Nicotinic

GGGG

LG

Glutamate NMDAAMPAKainate

Metabotropic

LGLGLGG

GABA AB

LGG

(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 junction)

• Autonomic NS Ganglia Parasympathetic NS--- Neuroeffector junction

Few sympathetic NS – Neuroeffector junction• Central N.S. - widespread

HippocampusHypothalamus ~

Ach ReceptorsAch Receptors• ACh is excitatory or inhibitory, depending on organ

involved.

– Causes the opening of chemical gated ion channels.• Nicotinic ACh receptors:

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

• Muscarinic ACh receptors:

– in the plasma membrane of smooth and cardiac muscle cells,

– in cells of some glands .

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)

Ligand-Operated ACh Channels

N Receptor

Acetylcholine Neurotransmission

• “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 (sweat glands,

skeletal muscle blood vessels - dilation)

G Protein-Operated ACh Channel

Acetylcholine Neurotransmission

• “Muscarinic” subtype: M2

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

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

Cholinergic Agonists

• Direct– Muscarine – Nicotine

• Indirect– AChE Inhibitors ~

Cholinergic Antagonists

• Direct Nicotinic - Curare Muscarinic - Atropine

(2) Monoamines as NT

Monoamines

• Catecholamines – Dopamine - DANorepinephrine - NEEpinephrine - E

• Indolamines （吲哚胺） - Serotonin - 5-HT

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

Epi1

G protein

PLC IP3

Ca+2

Adrenergic Neurotransmission2 Receptor

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

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

insulin secretion

Adrenergic Neurotransmission

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

Mechanism of Action ( receptor)

Adrenergic Neurotransmission

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

Adrenergic Neurotransmission

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

(3) Amino Acids as NT

• Excitatory Amino Acid (EAA)• Glutamate acid and aspartate acid• Inhibitory AA• gamma-amino-butyric acid (GABA) and

glycine:

GlutamateGlutamateNeurotransmitter at 75-80% of CNS synapses

Synthesized within the brain from – Glucose (via KREBS cycle/α-ketoglutarate ， a-酮戊二酸 )– Glutamine （谷氨酸盐） (from glial cells)

Actions terminated by uptake through excitatory amino acid transporters (EAATs) in neurons and astrocytes

124

Glutamate Receptor Subtypes

Ionotropic Glutamate Receptors

127

NMDA receptor as a coincidence detector : requirement for membrane depolarization

128

NMDA receptor uses glycine as a co-agonist

129

NMDA receptor channel is blocked by phencyclidine (苯环已哌啶， PCP)

Glutamate

non-NMDA receptors NMDA receptors

Na+ channelsopen Ca2+ channels open

(Mg2+ blockade)

depolarizationremovesblockade

Ca2+ enterswhen Mg2+

is removed

Ca2+dependentK+ channels

open

repolarization

postsynapticeffects

(learning)

reinstates blockade

a b c

a. Non-NMDA Na+ channels open, Na+ enters and depolarizes membrane

b. Mg2+ blockade of NMDA Ca2+channels removed by membrane depolarization; Ca2+enters

c. Ca2+ dependent K+ channels open; membrane repolarized

d. Mg2+ blockade reinstated

d

132

Gamma Aminobutyric acidGamma Aminobutyric acid(GABA)(GABA)

inhibitory neurotransmitter of CNS and retina.

formed by decarboxylation of glutamate .

three types of GABA receptors

– GABAA & B receptors are widely distributed in CNS.

– GABAC are found in retina only

133

NH2 – CH – CH2 – CH2 - COOH

COOH

NH2 – CH2 – CH2 – CH2 - COOH

Glutamic acid decarboxylase (GAD)

Glutamate GABA

GABA Synthesis

134

135

Subunit composition of ionotropic Subunit composition of ionotropic GABAGABAAA receptors receptors

Five subunits, each with four transmembrane domains (like nAChR)

Most have two alpha (α), two beta (β), one gamma (γ) subunit

α2 β2 γ1 is predominant in mammalian brain but there are different combinations in specific brain regions

136

Modified from nAChR, G and G 2011

137

138

The metabotropic GABAThe metabotropic GABABB receptor receptor

GPCRs Largely presynaptic, inhibit transmitter release Most important role is in the spinal cord

(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.• Hydrogen Sulfide (H2S)

SYNAPTIC PLASTICITYSYNAPTIC PLASTICITYPart III

Synaptic PlasticitySynaptic Plasticity Concept

– the ability of the synapse to change in strength in response to either use or disuse of transmission over synaptic pathways

Classification– Short term Plasticity (paired-pulse facilitation, short-term

potentiation, synaptic depression)– Long-term Plasticity

Long-term potentiation (LTP) Long-term depression (LTD)

I. The size of synaptic potentials can be modulated: • by regulating the amount of transmitter released at the synapse • by regulating the size of the current generated by postsynaptic

receptors.

II. Short term modulation (msecs - minutes)• Mechanism: are almost always presynaptic.

• Paired-pulse facilitation (~10 to 100 msecs)• Synaptic depression (50 msecs to mins)• Post-tetanic potentiation (mins)

III. Long-term plasticity• Mechanisms: complex and usually both pre- and postsynaptic

• LTP (30 minutes to years)• LTD (30 minutes to years)

Presynaptic vs. Postsynaptic

Facilitation and DepressionFacilitation and Depression

Facilitation of Transmitter ReleaseFacilitation of Transmitter Release

Cause: increased mean number of quanta of transmitter released by the presynaptic terminal, probably by increasing the probability of release and perhaps increasing the number of release sites.

Depression of Transmitter ReleaseDepression of Transmitter Release

caused by depletion of vesicles from the presynaptic terminal during the conditioning train, and reduced release efficacy.

GENERAL PRINCIPLES OF GENERAL PRINCIPLES OF THE REFLEX (SYNAPTIC THE REFLEX (SYNAPTIC TRANSMISSION)TRANSMISSION)

Part IV

Special Characteristics of Special Characteristics of Synaptic Transmission Synaptic Transmission

One way conduction Delay, 0.5 ms every synapse Summation and occlusion Change of frequency Afterdischarge and feedback Localization and generalization Fatigue Affected by

– acidosis and alkalosis– Hypoxia– Drug

OcclusionOcclusion

AfterdischargeAfterdischarge