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Lecture 2

NROC69H3 Lecture Notes - Lecture 2: Vesicle Fusion, Porosome, Chemical Synapse

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Michael Inzlicht

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Lecture 2: Neurotransmission
Chemical neurotransmission
Action potential down an axon to the nerve terminal
Opening of voltage-gated Ca 2+ channels in the presynaptic terminal
This allows the influx of Ca 2+
They float into the terminal
Ca 2+ leads to synaptic vesicles
Neurotransmitters bind to plasma membrane and release them into synaptic cleft
Post synaptic receptor neurotransmitters gets diffused ** happens in less than 1 ms
Other neurotransmitters either get taken back up or they get degraded
Some of them move away in other areas ** volume transmission
They then diffuse across to bind to postsynaptic receptors either ionotropic or
Early studies on Neurotransmitter release
Fatt & Katz: discovered a spontaneous miniature end plate potential (MEPPs) of ~0.5 mV
They found this spontaneous MEPP at the neuromuscular junction of a frog during
resting state
There was no stimulation but a 0.5 mV at resting phase
Presynaptic depolarization stimulation of the motor neuron increased the frequency
occurrence of MEPP but it did not change their amplitude suggesting 1 Ach
binding of 1 Ach receptor
However, if MEPP is manipulated with either nAch Receptor blocker or
acetylcholinesterase , Ach break down then the MEPP amplitude decreased
Ach release, ach receptor binding leads to MEPP
Suggesting MEPP must be reflecting the opening of many individual Ach receptors rather
than one since amplitude decreased more MEPP more amplitude
When motor neuron is stimulated under condition that are unfavorable for
neurotransmitter release (low Ca 2+), the EPP fluctuated in a stepwise manner
Smallest evoked EPPs were approx. the size of an MEPP & other EPPs were of sizes at
integral multiples of MEPPs (doubles, triples, quadruples …)
Quantal model of transmitter release
Quantal hypothesis, neurotransmitters are release from the presynaptic terminal in
separate units or Quanta
Quantum is a discrete and Quanta 100s at once

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Neurotransmitter release separated you get the response on the EPP; example: 2
neurotransmitter release a defined EPP
MEPP is a response to a spontaneous release of a single quantum building block of
EPP in the absence of action potential, ach leaks into the neuromuscular junction
causing very small depolarization in the postsynaptic
EPP is a response to some 100s of these quanta being released these are the binding
of neurotransmitters at the post synaptic terminals; these neurotransmitters binding to
postsynaptic receptors will then cause depolarization in the postsynaptic terminals
EPP at threshold level release of 100s MEPP quantum
Ca 2+ controls the release probability of the quanta such that at normal levels, there
would be sufficient Ca 2+ influx to release about a 100 quanta to generate an EPP of 40-
50 mV
However, at low Ca 2+ levels there would be a failure of release as well as small EPPs
As shown in the graph below:
Anatomical evidence of vesicular/quantal release
At the neuron muscular junction, a single Ach channel opens and generates ~0.5 uv
(micro volts)
Therefore, a quantal size of 0.5 mv MEPP it should open 1000 Ach channels
Every Ach channel require 2 Ach molecules
Some of these molecules will be destroyed by esterase or will be lost in the synaptic cleft
Therefore, an estimate of 5000 Ach molecule is needed overall
A synaptic vesicle is estimated to contain about 1000-4000 molecules
A good correspondence between the number of Ach molecules in a quantum and the
amount of Ach in a vesicle
If K+ channels are blocked then the Action potential is broadened and number of quanta
can be increased
After freezing the membrane, they found holes in the active zones, which were vesicles
They found number of fused vesicles matched the number of quanta measured from the
They also found pits outside of the cell and figured these were vesicles that can be

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The vesicles fuse fully with the membrane at the active zone, and that the membrane is
then taken from a region of the presynaptic terminal away from the active zone and used
to form new vesicles which are then filled with synaptic transmitter molecules known as
full fusion model
Another evidence to know it’s a full fusion evidence, is knowing the incorporation of
vesicle membrane into the cell membrane leads to an increase in the total cell surface
area of the presynaptic membrane given the capacitance measure is a function of the
membrane surface area and the membrane capacitance Cm
Cm is likely to remain constant however; increase in capacitance measure is likely to
reflect the full fusion
An example used to prove that statement was “whole cell patch clamp”
A small part of the membrane of an active vesicle fuses with and forms a pore through
the region of the presynaptic terminal facing the synaptic cleft, the vesicle discharges the
transmitter molecules into the synaptic cleft, it then vesicle then separates itself from the
membrane and moves to the interior of the bouton to have its store transmitter molecules
refilled. This rapid mechanism is called kiss and run model
Another evidence to know it’s a kiss and run model - a low level of signal, probably
representing leakage of neurotransmitter through a small flickering fusion pore (100 ms)
and leads a spike that results from the rapid dilation of the fusion pore and hence the
release of the remaining contents of the granule
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