Synaptic Plasticity Flashcards by Thomas Prud'homme

What is M=NPQ?

Formula for synaptic strength

P= Probability of release of a synaptic vesicle after an action potential (ranges from 0 to 1)
Q= Amplitude of the post-synaptic potential (PSP) resulting from the release of one vesicle.
N= number of vesicle release spots.
M is term for size of synaptic strength

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What 3 factors can influence the probability of vesicle release?

Amount of Calcium entering with an action potential: More calcium, more release

Number of primed vesicles

Coupling of Calcium entry to fusion of the vesicle; More coupling, more release

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What can be inferred from a readily releasable pool procedure (RRP)?

The RRP can be measured using an independent way of releasing vesicles, such as hypertonic shock that disrupts the membrane.
This releases all vesicles that are primed

PROVIDES A MEASURE OF P

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How can P be modulated?

PPF, PPD, PTP, modulatory neurotransmission (e.g. STF in aplysia)

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What determines whether paired pulse facilitation or depression occurs?

PPF occurs if initial probability of release is low
PPD occurs if initial probability of release is high

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How can PPF be used to probe whether a change in synaptic strength results from a change in P or Q?

If there is increased synaptic strength but no change in PPF, it means that the underpinning change comes from Q, not P

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If there is an increase in PPF, this means p _____
If there is a decrease in PPF, this means p _____
If there is no change in PPF, one can argue that p is _____.

If there is an increase in PPF, this means p decreased
If there is a decrease in PPF, this means p went up
If there is no change in PPF, one can argue that p is unchanged.

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What is PPF due to?

residual calcium from previous firing

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What sensor is mediating PPF? Why?

Syt 3 and 7 bc. sensitive to small amounts of calcium.

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True or false: In PPF, calcium binding to just the Syt 7/Syt 3 releases VS.

False: Calcium binding to just the Syt 7/Syt 3 complexin site makes the vesicle more primed, but is not sufficient for fusion (need calcium binding to Syt 1,2,9 site as well)

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What variable mainly influences PPD?

Time

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True or false: The higher the probability of release, the more pronounced depression will be.

True, as more of the RRP will be secreted.

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Is post-tetanic potentiation also relying on residual calcium?

Yes, indirectly

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What are three calcium sensors involved in mediating PTP?

Munc13
PKC
Synaptotagmin 3

BUT THESE ARE CELL SPECIFIC

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What does Syt3/7 increase during stimulus?

RRP

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What is EGTA?

high affinity calcium sensory competing with Syt3 for clacium -> high affinity like Syt 7!!!

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How can Munc13 increase RRP in PTP?

Munc13 binds calmodulin = calcium sensitivity -> calcium binding would accelerate Munc13’s ability to remove the inhibitory effect of Munc18 on syntaxin = increase in RRP

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How can unc-13 be regulated to increase priming? Is it important for PTP?

DAG can bind to C1 domain of unc-13 and increase priming

PKC also phosphorylates both munc13 and munc18, promoting priming

YES

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What is the time course of involvement of Munc13 and Syt3 during PTP?

During stimulus train Syt is important
Munc13 important afterward bc. binds calcium for longer

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In terms of homeostasis, why are PPF and PTP important?

increasing probability of release when the neuron is firing is an attempt to keep p constant during a long train of action potentials

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Short-term facilitation in aplysia is related to cellular habituation or sensitization?

Sensitization

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Short-term facilitation is caused by an increase in P or Q?

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Explain the cascade resulting in STF (from shock to release of transmitter)

Shock -> release of 5-HT -> G-prot -> cAMP -> PKA -> closing of K+ via phosphorylation -> slow repolarization after AP -> broader AP -> increase calcium influx -> more transmitter release

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True or false: Amplitude of miniature EPSPS (minis) are most often probes for postsynaptic changes

Yes, but sometimes vesicle content can change (e.g., changing uptake rate)

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RRP is increased after STF, what does that indicate?

In addition to be caused by a larger calcium influx, STF is also caused by increase in priming

Is short term depression acting directly on RRP? How can it be reversed?

No, RRP is intact in depression -> therefore caused by a loss in calcium secretion coupling, which might be due to an untethering of the calcium channel and SV PKC can restore calcium depression coupling at depressed synapses

What properties are required of a physiological basis for memory

Persistence Input Specificity Associativity

What kind of stimulation does it take to induce LTP?

Tetanic stimulation (100Hz) or Theta-Burst stimulation

What molecular structure mediates the associativity of LTP?

NMDA receptors (coincidence detection)

Why does LTP require calcium? And what allows the influx of calcium?

NMDA receptors allow Ca influx -> activation of CamKII

How does LTP decrease failure rate?

By upregulating AMPA receptors in the postsynaptic neuron

What is the evidence that LTP is not caused by increase in P?

Only increase in AMPA response (more vesicles released would not discriminate which receptor gets activated)

How can LTP "unsilence" AMPA postsynaptic responses?

In synapses that express no AMPA receptors, expression of AMPA via NMDA increases the responsitivity of the postsynaptic neuron by 100% from 0%.

What channel property of AMPA and NMDA allows to record NMDA currents almost entirely independently from AMPA currents?

AMAP currents shut off rapidly, while NMDA currents last longer -> simply wait for the AMPA currents to be off to record NMDA currents WITH magnesium block and CHANGING input voltage to separate NMDA (+40) and AMPA (-60) currents

What is the pathway by which LTP leads to the insertion of more AMPA receptors

NMDA -> CamKII -> PKC -> substrate phosphorylation -> AMPA insertion

How can you measure AMPA-R insertion during learning?

Use AUDITORY FEAR CONDITIONING = one-trial learning that takes place in the lateral amygdala where auditory inputs from the thalamus project Need a way to distinguish newly inserted AMPA-Rs from previously present AMPA-Rs -> ELECTROPHYSIOLOGICAL TAGGING – viral overexpression of GluA1 results in the formation of GluA1 homotetrameric AMPA- Rs that exhibit inward rectification. Normally AMPA-Rs are heterotetramers and non-rectifying.

True or false: Preventing new GluA1 insertion was sufficient to prevent learning during fear conditioning.

True.

How is L-LTP induced?

Multiple spaced trains of high-frequency stimulation

What intracellular process does L-LTP require?

CREB activation and dendritic protein synthesis

By which protein kinase is CREB phosphorylated by?

PKA

L-LTP shows synapse specificity, how possible since in involves protein synthesis?

synaptic tagging: L-LPT induces expression of "goodies" (plasticity related proteins) + Synapse would be tagged by initial AMPA trafficking event = L-LTP

What characterizes a successful synaptic capture in the case of L-LTP?

Strong L-LTP induction at synapse A = prod. of goodies + tag Weak E-LTP induction at synapse B = no prod. of goodies + tag Goodies expressed from strong L-LTP induction at synapse A will be capture BOTH by the tags of synapses A AND B

What kind of stimulation provokes LTD?

Low freq. stimulation

Is the downstream pathway of LTD similar to LTP?

Calcium is also needed in LTD, but afterward phosphatases and not kinases are the effectors

How is LTD ultimately implemented?

Endocytosis of AMPA receptors

What determines whether LTP or LTD occurs?

Intracellular concentration of calcium (det. by freq. of stimulation) Kinases haev low. calcium affinity = requires a lot of calcium = intense stimulation = LTP Phosphatases have high calcium affinity = requires a little bit a calcium = weak stimulation = LTD

Which phosphatase is known to play a role in LTD?

Calcineurin

Under which more realistic conditions than trains of stimulus are LTP and LTD happening? What is the name of the process?

Spike timing-dependent plasticity coordinates pre-synaptic activity with post-synaptic firing

Pre- before post- results in ____ Post- before pre- results in ____

Pre- before post- results in LTP Post- before pre- results in LTD

What property of action potential is particularly important for spike timing-dependent plasticity?

Back propagation to the dendrites (synapse location)

If 100% is the theoretical sum of calcium entry from EPSP and AP when measured independently, how much calcium do you get when: AP comes before EPSP EPSP comes before AP

AP (post) comes before EPSP (pre) = 50% = LTD EPSP (pre) comes before AP (post) = 150% = LTP

Are LTD postsyn or presyn at mossy fiber synapses? Provide respective pathway.

Presyn. LTP = presyn. influx of Ca = activation of AC1 -> cAMP -> PKA = increase release prob. LTD = glu retroactivating presyn. mGluR2 -> inhibition of AC1 -> cAMP -> PKA = decrease release prob.

Is LTD at the cerebellar synapse (PC-PF) postsyn. or presyn.? Provide pathway. What is counter-intuitive about this mechanism?

Postsyn. mGluR activation postsyn. -> PLC -> PKC -> phosphorylation (COUNTER-INTUITIVE) of AMPA receptors C-tails -> internalization of AMPAr

Endocannabinoids usually increase or decrease transmitter release? Are they acting pre- or post-synaptically?

Endogenous cannabinoids are released presynaptically and act retrogradely on CB1 receptors to generate different forms of synaptic depression: depolarization-dependent suppression of inhibition (DSI) depolarization-dependent suppression of excitation (DSE) LTD

How is CB1 activation preventing presyn. transmitter release?

CB1 G prot. blocks calcium entry pre syn.

Name one blocker of CB1r.

Rimonabant.

What is the goal of homeostasis of neural activity?

Reach a target firing rate that lays between seizure and cell death

With neuronal cultures, how can you demonstrate activity homeostasis?

Adding TTX, washing off = increase in spike activity Adding bicuculline (GABA antagonist silencing inhibition, so increasing excitability), washing off = decrease in spike activity

Is non-Hebbian plasticity (homeostasis) driven by change at specific synapses? On what molecular mechanism does it rely on? How does synaptic scaling relate to that?

No, whole circuit modification Large scale trafficking of AMPA receptors Synaptic scaling = all synapses of a regulated network conserve their relative synaptic strengths and are all regulated in the same manner (increase, decrease)

Are NMDA receptors necessary for homeostatic plasticity?

In inhibitory synapses, what receptors get regulated?