The document outlines the principles of synaptic transmission, differentiating between electrical and chemical synapses, and discussing neurotransmitter types and their receptors. It covers the mechanisms of neurotransmitter release, synaptic integration, modulation, and neurotransmitter recycling, along with details on synaptic plasticity. Additionally, it highlights various neurotransmitter categories and their functions, emphasizing the roles they play in learning and memory.

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NM3: SYNAPTIC TRANSMISSION

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Objectives
• General concept of synaptic transmission
• Electrical synapse vs. chemical synapse
• Synaptic integration and modulation
• Neurotransmitters and their receptors:
▫ Classical and non-classical

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Introduction
• Transfer of electrical signals from one cell to
another:
▫ Nerve to nerve
▫ Nerve to muscle
▫ Sensory receptors to nerves
▫ Nerves to other cells e.g. glia cells
• Electrical synapse vs. chemical synapse

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Electrical synapse
• Aka gap junctions
• Low resistance pathway for:
▫ Current flow
▫ Sharing small molecules between the two cells
• Plaque-like structures with closely apposed cell
membranes filled with electron dense material.

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Properties
Fast (no synaptic delay)
Bidirectional
Low pass filters: transmit slow electrical events
more readily
Demonstrate specificity in gap junction coupling
• Main function is to synchronize activity.

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Modulation
• Properties altered by:
▫ Intracellular pH, voltage and calcium
▫ G protein coupled receptors
▫ Connexins have phosphorylation sites
• These alter gap junctions functions by:
▫ Changing the channel conductance
▫ Formation of new gap junctions
▫ Removal of existing ones

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Chemical synapse

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Chemical synapse
• Earlier demonstrations by Otto Loewi in frog’s heart
and vagus nerve
• Typically:
▫ Axodendritic / axosomatic
• Others:
▫ Axoaxonic, dendrodendritic, dendrosomatic
• A synapse could be: mixed synapse, serial synapse,
reciprocal synapse and some form a glomerulus

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Key words
Presynaptic terminal
Synaptic cleft
Neurotransmitters :classical vs. non classical
Postsynaptic terminal
Metabotropic vs. ionotropic receptors
EPSP & IPSP

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Use the above Key words to summarize
Synaptic transmission

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Transmitter release
• Calcium entry via voltage gated channels is the trigger
• Explain the basis of suppression potential?

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Vesicle hypothesis of NT’s release
• NT’s are released in a quantal nature
• EPSP results from summation of the effect of all the
NT’s released.
• The lowest EPSP (mEPP) result from effect of a
number of NT’s released from one vesicle.
• mEPP is the smallest EPP evoked under low
calcium levels

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Vesicular release
• Docking Priming Fusion
→ →
• Involves specialized proteins called SNARE proteins
▫ v-SNARE: synaptobrevin
▫ t-SNARE: syntaxin & SNAP 25
• Involved in docking and priming
▫ Targeted by botulinum toxin.
• Fusion is mediated by a calcium sensor protein called
synaptotagmin at the active zone after local calcium levels
↑

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Recycling of synaptic vesicles
• 2 mechanisms:
▫ Endocytic pathway (fusion & collapse)
▫ The kiss & run fusion

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Post synaptic potentials
• EPP
• EPSP
• IPSP
• Safety factor: ratio of synaptic potential to the
amplitude needed to reach threshold
▫ Higher for muscles than neurons
• Distinguish fast from slow synaptic transmission

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• The flow of ions across an ion channel is dictated by the
electrochemical gradient and predicted by:
Ix = gx X (Vm - Ex)
• The net inward current is called EPSC
• The potential at which there is no EPSC/EPSP is called
the reversal potential.
• Why does reversal potential occur in ligand gated and not
voltage gated channels?

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EPSP IPSP
Depolarizing Depolarizing or hyperpolarizing
↑ probability of an AP ↓ probability of an AP
Reversal potential is more positive
than threshold: {~0 mV (+/- 10 mV)}
Reversal potential is more negative
than threshold
Main channels: Na+ and K+ Main channels: K+ and Cl-

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Activity
• Discuss the differences between an electrical
synapse and a chemical synapse.

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SYNAPTIC INTEGRATION
• Spatial location in the dendritic tree is an
important determinant of efficacy
▫ Temporal summation
▫ Spatial summation
▫ Shunting effect
• How do IPSPs & EPSPs integrate?

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• Dendrites and somas of most neurons contain
some active elements (gated channels) that can
amplify & alter the EPSPs & IPSPs. E.g.
▫ Na+ & Ca++ voltage gated channels activated by
EPSPs….
▫ Ca++ activated K+ channels…???
• Can a hyperpolarizing potential lead to a spike?

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Modulation of synaptic activity
• The strength of individual synapses can vary as a
function of their use or activity.
• I’m sure you read in advance, so in appreciation
let’s discuss the following:

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Paired pulse facilitation (PPF)

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Posttetanic potentiation
• Mainly due to changes in the presynaptic
terminal
• Increased quanta release of NT’s due to
increased intracellular Ca++ from the residual
Ca++ from the preceding stimuli

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Synaptic depression
• Presynaptic: depletion of synaptic vesicles
• Postsynaptic: desensitization of receptors

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• What happens when potentiation and
depression occur in the same synapse?

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Presynaptic receptors
• Can modulate neurotransmitter release
• Presynaptic inhibition
• Autoreceptors; serial synapse; nonsynaptically
acting NT’s.

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Activity
• Discuss long term potentiation and long term
depression and the role of calcium and nitric
oxide in these and in memory and learning.

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NEUROTRANSMITTERS

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Introduction
• Mediate chemical signaling
• Criteria:
▫ Synthesized by cell and present in presynaptic
terminal
▫ Released upon depolarization
▫ Have receptors on the postsynaptic membrane
• >100 potential NT’s

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Classification
• Small molecule transmitters
▫ Acetylcholine
▫ Amino acids
▫ Biogenic amines
▫ Purines
• Peptides
• Gaseous transmitters
• Classical vs. Non classical neurotransmitters

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A. SMALL MOLECULE TRANSMITTERS
1. ACETYLCHOLINE
• Location: both CNS & PNS e.g. NMJ
• Synthesis: acetyl coA + Choline with the aid of
cholineacetyltransferase.
• Fate: Degraded by acetylcholinesterase to
acetate & choline (reuptake for recycling)

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• Receptors:
• Nicotinic:
▫ Ionotropic of cys loop superfamily
▫ Pentamers
▫ CNS (3α,2β), NMJ (2α,β,δ,ε)
▫ EPSP via cation selective channel
• Muscarinic:
▫ Metabotropic via different types of G proteins
▫ Subtypes M1-5

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2. Amino acids
a. Glutamate:
• Excitatory
• Precursor to GABA
• Fate???

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b. GABA & Glycine
• Inhibitory
• GABA:
▫ From glutamate (glutamic acid decarboxylase)
▫ In spiny neurons of striatum and purkinje of
cerebellum
• Glycine:
▫ Generally inhibitory
▫ Excitatory at NMDA receptors as a cotransmitter

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• Fate:
• GABA: uptake to nerve terminals and glia by
high affinity Na+-Cl- coupled symporter i.e.
GAT1,2,3,4
• Glycine: GlyT1&2 which is also a Na+-Cl-
coupled symporter.

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3. Biogenic amines
• E, NE, Dopamine, Serotonin, Histamine
• Fate:
▫ Reuptake into glia & neurons via the Na+-Cl-
coupled transporter
▫ Catecholamines then degraded by MAO & COMT

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• Location in CNS varies and indicates correlation
with their functions.
▫ NE- locus ceruleus
▫ Serotonin: Raphe nuclei
▫ Histamine: tubomammilary nuclei of
hypothalamus
▫ Dopamine: substantia nigra
▫ Epinephrine: autonomic nuclei

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4. Purines
• ATP:
▫ Transmitter or cotransmitter
▫ Present in all synaptic vessicles
▫ Glia cells may also release ATP
▫ Fate: broken down by ATPases and
5’nucleotidases to adenosine (reuptake by
presynaptic terminal via adenosine receptors)

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B. PEPTIDES
• >100 neuropeptides
• Main transmitter or co transmitter
• Compare and contrast the classic and peptide
neurotransmitters?

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Opioid peptides
• Opiates vs. opioids
• 3 major classes:
▫ Enkephallins
▫ Endorphins
▫ Dynorphins
• Widely distributed in CNS & GIT
• Analgesics

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Substance P
• 11 aa; in CNS & GIT
• Pain transmission and affect smooth muscle
functions
• Enkephallins inhibit Sub P at the dorsal root
ganglia to inhibit pain pathways

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C. GAS NEUROTRANSMITTERS
• Widens scope of synaptic transmission
• NO, CO
• No receptors
• NO:
▫ Synthesized upon depolarization by NO synthase
▫ As a signal transduction molecule regulating the
guanylyl cyclase and acting on vascular smooth
muscles

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RECEPTORS
• IONOTROPIC:
• Ligand gated ion channels
• 4 superfamilies:
▫ Cysloop super family (Ach, Serotonin, GABA,
Glycine)
▫ Glutamate
▫ ATP
▫ Transient receptor potential chanels (pain &
thermal stimulus)

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GABA & Glycine
• GABA a,c and glycine:
▫ Cysloop ionotropic receptors
▫ Cl- channels
▫ GABA a targeted by Benzodiazepines &
Barbiturates
• GABA b:
▫ Metabotropic- GTP – activates K+ chanels and
inhibits Ca++ chanels

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Glutamate
• Metabotropic:
▫ Grp I (postsynaptic), Grp II,III (presynaptic)
• Ionotropic:
▫ AMPA & Kainase
▫ Cationic selective chanels Na+, K+, +/- Ca++
▫ NMDA: differs in that it
 Requires glutamate & glycine to bind to open
 Display voltage sensitivity due to Mg++ blockade
 Permeable to calcium & can act as a 2nd
messanger

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Purine (ATP) receptors
• Ionotropic (P2x): cation sensitive (Na+, K+,Ca+)
• Metabotropic (P2y):
▫ G coupled to activate K+ chanells & modulate both
NMDA & voltage gated Ca++ chanells
• Adenosine receptors:
▫ Presynaptic
▫ Inhibits synaptic transmission by inhibiting Ca++
influx

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Biogenic amines receptors
• All metabotropic type receptors except one class
of serotonin receptors (5HT3) which are part of
the cysloop ionotropic family

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Neuropeptide receptors
• All metabotropic like biogenic amines
• Are exposed to lower agonists concentration
• More sensitive to their agonists

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Gas neurotransmitters receptors
• Do not bind to receptors
• NO affects receptors by:
▫ Activating enzymes involved int the 2nd
messanger
cascade e.g. guanylyl cyclase
▫ Modifying the activities of other proteins by
nitrosyllating them e.g. NMDA receptors, Na+-K+
ATPase pump

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Activity
• Discuss the NT’s one after the other under the
following subheadings:
▫ Synthesis
▫ Location
▫ Receptors
▫ Fate
▫ Activity/effects
▫ Classification
▫ Clinical application
• Discuss synaptic plasticity and learning

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“Be afraid of remaining stagnant not slow progress.”
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