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Synaptic Synaptic TransmissionTransmission

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Synaptic contactsSynaptic contacts Axodendritic – axon to Axodendritic – axon to

dendritedendrite Axosomatic – axon to Axosomatic – axon to

somasoma Dendrodendritic – Dendrodendritic –

capable of transmission capable of transmission in either directionin either direction

Axoaxonal – may be Axoaxonal – may be involved in presynaptic involved in presynaptic inhibitioninhibition

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Structure of the Structure of the SynapseSynapse

Synaptic cleft

Synaptic vesicles

Button

microtubules

Golgi complex

Mitochondrion

Dendriticspine

Presynaptic membrane Postsynaptic membrane

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Release of NeurotransmitterRelease of Neurotransmitter Exocytosis Exocytosis – the process of – the process of

neurotransmitter releaseneurotransmitter release The arrival of an AP at the terminal opens The arrival of an AP at the terminal opens

voltage-activated Cavoltage-activated Ca++++ channels. channels. The entry of CaThe entry of Ca++++ causes vesicles to fuse causes vesicles to fuse

with the terminal membrane and release with the terminal membrane and release their contentstheir contents

http://www.tvdsb.on.ca/westmin/science/sbioac/homeo/synapse.htm

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Ca+

Terminal Button

Ca+

ExocytosisExocytosis

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Neurotransmitter MoleculesNeurotransmitter Molecules

Two basic categories:Two basic categories:– Small moleculeSmall molecule

Synthesized in the terminal button and Synthesized in the terminal button and packaged in synaptic vesicles.packaged in synaptic vesicles.

– Large molecule (peptide)Large molecule (peptide) Assembled in the cell body on ribosomes, Assembled in the cell body on ribosomes,

packaged in vesicles, and then transported packaged in vesicles, and then transported to the axon terminal.to the axon terminal.

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Types of SynapsesTypes of Synapses

DirectedDirected – the site of – the site of neurotransmitter release and neurotransmitter release and receptor activation are in close receptor activation are in close proximity.proximity.

NondirectedNondirected – the site of release is at – the site of release is at some distance from the site of some distance from the site of reception.reception.

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Presynaptic activation of ACh muscarinic receptors suppresses synaptic transmission at intrinsic fiber synapses but not at afferent fiber synapses.

Postsynaptic activationsuppresses normaladaptation of pyramidal cell firing by blocking voltage- and Ca+-dependent K+ currents.

Combined, these effects may prevent recall of previous memory from interfering with the learning of new memories.

(Adapted from Hasselmo, 1995)

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Receptor-neurotransmitter Receptor-neurotransmitter interactionsinteractions

Released neurotransmitter produces Released neurotransmitter produces signals in postsynaptic neurons by binding signals in postsynaptic neurons by binding to receptors.to receptors.

Receptors are specific for a given Receptors are specific for a given neurotransmitter.neurotransmitter.

LigandLigand – a molecule that binds to another. – a molecule that binds to another. A neurotransmitter is a ligand of its A neurotransmitter is a ligand of its

receptor.receptor.

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ReceptorsReceptors

There are multiple There are multiple receptor subtypesreceptor subtypes for each neurotransmitter molecule.for each neurotransmitter molecule.

Two general classes of receptors:Two general classes of receptors:

1.1. Ionotropic receptorsIonotropic receptors – associated – associated with ligand-activated ion channels.with ligand-activated ion channels.

2.2. Metabotropic receptorsMetabotropic receptors – associated – associated with signal proteins and G proteinswith signal proteins and G proteins

1.1. PostsynapticPostsynaptic

2.2. Presynaptic (autoreceptors)Presynaptic (autoreceptors)

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Deactivating Deactivating NeurotransmittersNeurotransmitters

As long as neurotransmitter is in As long as neurotransmitter is in the synapse, it is active – the synapse, it is active – activity must somehow be activity must somehow be turned off.turned off.

1.1. ReuptakeReuptake – neurotransmitter is – neurotransmitter is taken back into the presynaptic taken back into the presynaptic terminal.terminal.

2.2. Enzymatic degradationEnzymatic degradation – – neurotransmitter is broken neurotransmitter is broken down by enzymes. down by enzymes.

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Small-molecule Small-molecule Neurotransmitters Neurotransmitters

Amino acidsAmino acids – the building blocks of – the building blocks of proteinsproteins

MonoaminesMonoamines – all synthesized from a – all synthesized from a single amino acidsingle amino acid

Soluble gasesSoluble gases Acetylcholine (ACh)Acetylcholine (ACh) – activity – activity

terminated by enzymatic terminated by enzymatic degradationdegradation

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Amino Acid Amino Acid NeurotransmittersNeurotransmitters

Usually found at fast-acting directed Usually found at fast-acting directed synapses in the CNSsynapses in the CNS

GlutamateGlutamate – Most prevalent excitatory – Most prevalent excitatory neurotransmitter in the CNSneurotransmitter in the CNS

GABAGABA – – – synthesized from glutamatesynthesized from glutamate– Most prevalent inhibitory Most prevalent inhibitory

neurotransmitter in the CNSneurotransmitter in the CNS Aspartate and glycineAspartate and glycine

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MonoaminesMonoamines

Effects tend to be diffuseEffects tend to be diffuse CatecholaminesCatecholamines – synthesized from – synthesized from

tyrosinetyrosine– DopamineDopamine– NorepinephrineNorepinephrine– EpinephrineEpinephrine

IndolaminesIndolamines – synthesized from – synthesized from tryptophantryptophan– Serotonin (5-HT).Serotonin (5-HT).

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Acetylcholine and soluble Acetylcholine and soluble gasesgases

Acetylcholine Acetylcholine (Ach)(Ach)– Acetyl group + choline Acetyl group + choline – Neuromuscular junctionNeuromuscular junction

Soluble gasesSoluble gases – exist only briefly – exist only briefly– Nitric oxide and carbon monoxideNitric oxide and carbon monoxide– Retrograde transmission – Retrograde transmission –

backwards communicationbackwards communication

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Ca2+

Na+Glutamate

Polyamine

Zn2+

PCP

Mg2+

Glu

Glycine /D-Serine

Gly

PSD-95

L-Arginine

L-CitrulineCa2+

CaM

NO *

NOS

NMDA Receptor Activation NMDA Receptor Activation

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D-serine localization in rat brainD-serine localization in rat brain

What is the NMDAR System What is the NMDAR System and How Does it Function?and How Does it Function?

NMDA is a receptor for one NMDA is a receptor for one of the most prominent of the most prominent excitatory neurotransmitters excitatory neurotransmitters in the brain (Glutamate)in the brain (Glutamate)

NMDA Receptors require co-NMDA Receptors require co-activation of 2 ligands activation of 2 ligands (Glutamate and Glycine)(Glutamate and Glycine)

Ion channel opens allowing Ion channel opens allowing Na+ and Ca+ in and K+ outNa+ and Ca+ in and K+ out

NMDA Receptor DistributionNMDA Receptor Distribution

StriatumStriatum HippocampusHippocampus

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Pharmacology of Synaptic Pharmacology of Synaptic TransmissionTransmission

Many drugs act to alter Many drugs act to alter neurotransmitter activityneurotransmitter activity

AgonistsAgonists – increase or facilitate – increase or facilitate activityactivity

AntagonistsAntagonists – decrease or inhibit – decrease or inhibit activityactivity

A drug may act to alter A drug may act to alter neurotransmitter activity at any point neurotransmitter activity at any point in its “life cycle”in its “life cycle”

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Examples of AgonistsExamples of Agonists

Cocaine Cocaine - catecholamine agonist- catecholamine agonist– Blocks reuptake – preventing the Blocks reuptake – preventing the

activity of the neurotransmitter from activity of the neurotransmitter from being “turned off”being “turned off”

BenzodiazepinesBenzodiazepines - GABA agonists - GABA agonists– Binds to the GABA molecule and Binds to the GABA molecule and

increases the binding of GABAincreases the binding of GABA

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Examples of AntagonistsExamples of Antagonists

AtropineAtropine – ACh antagonist – ACh antagonist– Binds and blocks muscarinic receptorsBinds and blocks muscarinic receptors– Many of these metabotropic receptors Many of these metabotropic receptors

are in the brain are in the brain – High doses disrupt memoryHigh doses disrupt memory

CurareCurare - ACh antagonist - ACh antagonist– Bind and blocks nicotinic receptors, the Bind and blocks nicotinic receptors, the

ionotropic receptors at the ionotropic receptors at the neuromuscular junctionneuromuscular junction

– Causes paralysisCauses paralysis

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