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sequence of events of transmission at chemical synapses (5)

1) AP arrives at presynaptic bouton

2) depolarization of presynaptic membrane causes voltage-gated Ca channels to open, Ca flows into cell

3) increase cytosolic [Ca] MAY causes synaptic vesicle docked at active zone to fuse with plasma membrane
- neurotransmitter released into synaptic cleft
- does not occur with every AP

4) neurotransmitter binds to ionotropic and metabotropic receptors
- leading either directly or indirectly to opening of ion channels

5) postsynaptic current leads to postsynaptic potential
--> change in potential of postsynaptic membrane


neurotransmitter release probability is defined for individual release sites

- some synapses have multiple release sites
- release probability varies greatly between synapses

- Calyx of Held= 600 release sites, transmission at this synapse is very reliable


3 factors infuencing transmitter release probability

1) synaptic vesicle docking
- probability regulated by number of synaptic vesicles docked to active zone
- # docked SV, regulated by size of active zone, and/or size of recycyling vesicle pool

2) synaptic vesicle priming
- rate of priming is differential at low and high probability synapses, changing amount of SV available for immediate release
- ex: local increase in Ca or diacylglycerol facilitate ability of Munc13 to assist SNARE complex formation, increasing fraction of docked vesicles that are primed

3) Ca-dependent synaptic vesicle fusion
- differences in Ca influx through voltage-gated Ca channel and its coupling to SV may likewise contribute to variability in release probability


how does Ca-dependent synaptic vesicle fusion contribute to variability in transmitter release probability (3)

1) variability in Ca channel type and regulation

2) variability in localization of Ca channels relative to primed synaptic vesicles and the fusion machinery

3) variability in Can sensory affinity or amount of Ca sensor


how is neurotransmitter release probability subject to use-dependent changes?

short term plasticity of neurotransmitter release
- in response to repetitive stimulation, neurotransmitter release can either FACILITATE (release probability increases), or DEPRESS (release probability decreases with repeated stimulation)

facilitate= low probability
depress= high probability

- neurotransmitter release at most synapses is subject to both facilitation and depression


causes of short term depression of neurotransmitter release

- depletion of readily releasable pool of docked and primed synaptic vesicles

- postsynaptic receptors can undergo desensitization or saturation (all synaptic receptors already open, additional neurotransmitter no effect)


causes of short term facilitation of neurotransmitter release

- Ca ions remaining in terminal after repetitive stimulation, increasing aspects of exocytosis
(Ca stay in presynaptic terminal after AP)


time course of short-term facilitation and depression of transmitter release

- short time intervals

- depression within seconds- need to stimulate presynaptic terminal to see depression

- facilitation more short lived, needs to have 2 AP separeted by 1000s of milliseconds to see facilitation of release of 2nd AP
- short lived because Ca is released quickly from presynaptic terminal, when no residual Ca, there is no facilitation


what is paired-pulse facilitation/depression

- response to single previous stimulus is maximal if the second stimulus closely follows the first and decays rapidly with time (depression last longer that facilitation)


post-tetanic potentiation

form of facilitation lasting minutes
- follows prolonged stimulation at high frequency
- rely on processes stimulated by residual presynaptic Ca


4 sources of changes of neurotransmitter release in response to extrinsic modulation

- neurotransmitter release can be modulated acting on ionotropic/metabotropic receptors on presynaptic terminal

1) transmitter released from axo-axonic synapses
2) transmitter released from terminal itself
3) transmitter from adjacent synapses
4) neuromodulators released from postsynaptic neuron


example: GABAergic axo-axonic synapses attenuate transmitter release (spinal cord)

- activation of ionotropic receptors leads to chloride influx- hyperpolarizing terminal

- metabotropic receptors activate G-proteins, which direcly inhibit voltage-gated Ca channels


example: Metabotropic receptors on glutamatergic terminals attenuate transmitter release probability

- glutamate released from either same or adjacent terminals will bind to metabotropic receptors on that terminal and inhibit release- by inhibition of voltage-gated Ca channels through G-proteins

- metabotropic receptors usually only activated during prolonged high-frequency stimulation, leading to accumulation of glutamate in extracellular spaces due to overwhelmed glutamate re-uptake mechanisms


example: inhibition of GABA release by postsynaptic neuron

- in cerebellum and hippocampus
- release at GABAergic terminals can be inhibited by secretion of neuromodulator from postsynaptic neuron: endocannabinoids
- receptors activate G-proteins which inhibit voltage-gated Ca channels


spatial summation of coincident excitatory input

- postsynaptic potentials derived from activation of single synapses only reach anywhere from fraction of a millivolt to a few millivolts
- cannot elicit action potentials by themselves
- AP can be reached through spatial summation of simultaneously activated excitatory synapses


EPSPs often sum ____

and exception

- total depolarization is the arithmetic sum of the individuals EPSPs

- EPSPs of excitatory synapses that are close to each other on dendritic tree will sum sub linearly if simultaneously activated
- b/c the reduced driving force for ions passing through ligand-gated ion channels due to increased local depolarization


problem with dendritic cable filtering

- EPSPs undergo significant cable filtering on their way to dendrite to the soma: their amplitude decreases, their time course slows


2 ways distal synapses make themselves heard

1) EPSPs generated by activation of distal synapses are larger than EPSP generated by proximal synapses
- some neurons, due to greater # neurotransmitter receptors at distal synapses, creating greater synaptic conductances
- also due to smaller dendritic diameter in distal dendrites

2) dendrites have voltage-gated conductances
- if several synapses on same distal dendritic branch are synchronously activated, they will cause local depolarization, which will create dendritic spike amplifying depolarization created by EPSP


shunting effect of inhibitory synapses

- clamping the local membrane potential to reversal potential of its ion channels
- activated GABAergic synapses will cause more attenuation of EPSPs generated at more distal excitatory synapses (than ones proximally)

exception: inhibitory synapses closer to soma have more ay in how the post synaptic neuron fires than distal


when will facilitating synapses trigger AP in postsynaptic neuron?

- depressing synapses trigger

set of facilitating synapses with low initial transmitter release probability will trigger AP only if they are stimulated repetitively

- depressing synapse with high initial transmitter release probability tend to drive postsynaptic neuron through spatial summation of coincident EPSPs rather than through temporal summation during repetitive activity


What is the neurotransmitter release probability (Pr) of a synapse?

Which factors control Pr?

- The release probability is the likelihood with which an action potential elicits the release of neurotransmitter at a synapse.
- Pr has values between 0 (action potential never elicits release) and 1 (each action potential elicits release).

- Pr controlled by number of docked synaptic vesicles, speed of priming, factors affecting calcium influx through voltage-gated calcium channels and detection of
inflowing calcium by synaptotagmin.


Recordings of synaptic currents are made from a CA1
pyramidal neuron in the hippocampus while Schaffer collateral afferents are stimulated with extracellular electrodes. Repetitive stimulation at 50 Hz (action potentials elicited at 20 ms intervals, marked by arrowheads) elicit the excitatory postsynaptic currents
(EPSCs) shown on the right.

Why is the amplitude of the second EPSC larger than that of the first EPSC?

Why is the EPSC amplitude of the 10th EPSC smaller than that of the second?

What are possible mechanisms for these changes?

- The amplitude of the second EPSC is larger than that of the first EPSC due to facilitation of neurotransmitter release.
- Calcium entering the presynaptic neuron positively regulates synaptic vesicle docking and priming and increases the likelihood that synaptic vesicles fuse with the plasma membrane in response to the next action potential.
- The 10th EPSC is smaller than the second EPSC due to depression of neurotransmitter release.
- One possible reason for the decrease in release probability is the depletion of the readily releasable pool of synaptic vesicles


What is the effect of axo-axonic synapses containing GABA(A) and GABA(B) receptors, glutamate acting via presynaptic metabotropic glutamate receptors postsynaptically generated endocannabinoids on neurotransmitter release?

What are the mechanisms?

- GABA(A) and GABA(B) receptors at axo-axonic synapses, presynaptic metabotropic glutamate receptors, and endocannabinoid binding metabotropic receptors all inhibit neurotransmitter release.
- GABA(A) receptors conduct chloride, which acts to keep the membrane potential close to the reversal potential
for chloride, thus inhibiting depolarization and opening of voltage-gated calcium channels.
- GABA(B) receptors, metabotropic glutamate receptors, and endocannabinoid receptors activate G proteins which
bind to and inhibit voltage-gated calcium channels.


What is "cable filtering" in dendrites?

Which synaptic and dendritic mechanisms ensure that
distal synapses can affect postsynaptic action potential firing?

- EPSPs undergo electrotonic decay (get smaller) on their way along the dendrite to the soma.
- Distal synapses often have greater local EPSPs, often due to the presence of more neurotransmitter receptors, to partially compensate for larger electrotonic decay.
- Moreover, voltage-gated sodium and calcium channels in dendrites can amplify signals in distal dendrites if several synapses on the same dendritic region are activated