chapter 30
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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
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