Synaptic plasticity

Question 1

Forms of plasticity distinguished by:

Answer 1

Duration
* Direction of effect
* Source of induction
Site of expression

Question 2

Duration

Answer 2

• Short term – msec to minutes
• Long term – hours to days, weeks, or longer

Question 3

• Direction of effect

Answer 3

enhancement
- depression

Question 4

Source of induction

Answer 4

• homosynaptic –
  intrinsic to synapse
• heterosynaptic –
  third neuron involved

Question 5

Site of expression

Answer 5

• both homo- and heterosynaptic
  expression
• presynaptic – change in amount of transmitter released
• postsynaptic
• change in response to transmitter released
  → changes in sensitivity and
  number of receptors
• intracellular mechanisms that
  regulate membrane excitability
• Synaptic cleft – e.g. altered cell
  adhesion molecules (neuroligins,
  cerebellin1 etc.)

Question 6

Synaptic Facilitation

Answer 6

Increase in synaptic strength that results when action potentials occur in
rapid succession (few milliseconds)

• Saturation of calcium buffers
• facilitation calcium channels, and
• (residual) Ca++
  -dependent processes.

Question 7

Synaptic facilitation are a result of

Answer 7

prolonged calcium elevation (“residual calcium hypothesis”).
Ca2+ entry into the terminal is fast, but the return to resting levels is slower
→ residual Ca2+ lasts as long as PPF, ~10-1000 msec
→ more transmitter can be released by subsequent action potentials
* Target of action is likely synaptotagmin

Question 8

Synaptic depression

Answer 8

Reduction in synaptic strength during successive action potentials

• Depletion of readily releasable vesicles
• inactivation of release sites, and
• inactivation of calcium channels.

Question 9

Synaptic depression results from

Answer 9

progressive depletion of vesicle pool (and to lesser extent inactivation of
release sites, and inactivation of calcium channels)

Question 10

Rate of depression depends on

Answer 10

amount of transmitter released (the more is released initially, the less
is available on subsequent APs)

Question 11

lowering Ca2+ reduces

Answer 11

the probability of release and slows rate of depression

Question 12

Both Augmentation and Potentiation

Answer 12

enhance the ability of incoming calcium to trigger fusion of synaptic vesicles with the membrane.

• Increased quantal size
• Ca++-dependent increases in the probability of release
• facilitation of calcium channels, and
  alterations in trafficking mechanisms

Question 13

Augmentation

Answer 13

rises and falls over a few seconds

possible target: Munc-13 (helps with priming)

Question 14

post-tetanic potentiation (PTP)

Answer 14

asts over a time scale of tens of seconds to minutes

possible target: synapsin (facilitates trafficking from reserve pool)

Question 15

During repetitive synaptic activity
different forms of short-term
plasticity

Answer 15

interact

Question 16

Sensitization results from

Answer 16

activation of
the serotonergic modulatory
interneuron, which increases the EPSP at
the motor neuron → heterosynaptic

Question 17

Sensitization (short term)

Answer 17

5-HT (via a metabotropic receptor) activates Adenylyl-cyclase, which in turn increases cAMP, and then PKA.

Question 18

PKA has 2 effects in Sensitization

Answer 18

Closes K+ channels, leading to
broader spikes and more Ca2+ influx
→ more transmitter release

• PKA also directly increases the
  release of neurotransmitter

Question 19

Sensitization (long term – weeks)

after repeated pairings, PKA also
phosphorylate

Answer 19

s CREB (transcription factor)

Question 20

Sensitization (long term – weeks

CREB stimulates

Answer 20

ubiquitin hydrolase
→ keeps PKA persistently active
(degrades PKA’s regulatory subunit)

Question 21

Sensitization (long term – weeks)

C/EBP →

Answer 21

regulates activity of other
(unknown) genes that lead to structural
changes, i.e. growth of new synapses

Question 22

Hebb’s theory of synaptic plasticity

Answer 22

“Cells that fire together, wire together”

postulates that when one
neuron drives the activity of another neuron, the connection
between these neurons is potentiated

Question 23

Characteristics of (NMDAR-dependent) LTP

Answer 23

Input (synapse) specificity
Associativity
Cooperativity:
State-dependence

Question 24

Input (synapse) specificity:

Answer 24

LTP is restricted to active synapse

Question 25

Associativity

Answer 25

coincident activation of a weak pathway together with a strongly activated pathway will lead to LTP in the weak pathway.

Question 26

Cooperativity

Answer 26

coincident activation of several weak pathways may also act cooperatively to provide sufficient depolarization

Question 27

State-dependence

Answer 27

when an EPSP which in itself does not evoke LTP (e.g. low frequency stim) is paired with post-synaptic depolarization, LTP can be induced

Question 28

presynaptic LTP is characterized by

Answer 28

enhanced transmitter release

Question 29

2 possible mechanisms of Presynaptic LTP:

Answer 29

a large rise in presynaptic Ca2+ that activates adenylate-cyclase (AC), leading to a rise in cAMP and activation of protein kinase A (PKA), which regulates Rab3A (vesicle transport) * alternatively, the postsynaptic rise in Ca2+ can activate a retrograde signal, such as nitric oxide (NO)

Question 30

While induction entails the transient activation of CaMKII and PKC, maintenance of the early phase of LTP is

Answer 30

characterized by their persistent activation.

Question 31

# Induction and early phase of LTP (E-LTP, < 3 hours) During this stage, Protein kinase M zeta (a variant of PKC, which does not depend on Ca2+) and CaMKII become

Answer 31

autonomously active. Autonomously active CaMKII and PKC phosphorylate AMPA receptors for the expression of early-LTP: * First, and most importantly, they phosphorylate existing AMPA receptors to increase their activity. * Second, they mediate or modulate the insertion of additional AMPA-Rs into the postsynaptic membrane.

Question 32

Silent synapses

Answer 32

release glutamate, but they lack AMPARs on the postsynaptic membrane. show an NMDA current at depolarized potentials, but no AMPA currents close to resting potentia Only NMDARs are found in the postsynaptic membrane (bind/respond to glutamate). AMPARs are not completely absent, but located inside the postsynaptic cell, where they cannot detect extracellular glutamate.

Question 33

Activation of silent synapses is a proposed mechanism (and proof-of-concept) for

Answer 33

rapid increases in synaptic efficacy

Question 34

Calmodulin activates CaMKII, which phosphorylates and inserts

Answer 34

AMPARs into the postsynaptic membrane → unsilencing of silent synapse

Question 35

Long-term synaptic depression - LTD

Answer 35

occurs when a pathway is stimulated at a low rate (0.5-5 Hz) for a long time (10-15 min). Like LTP, LTD lasts for several hours, * is input specific, and * LTD can erase the increase in EPSP size resulting from LTP

Question 36

Long-term synaptic depression results mainly from a

Answer 36

decrease in postsynaptic AMPA receptor density

Question 37

LTD results from activation of

Answer 37

Ca2+-dependent phosphatases * protein-phosphatase-1 [PP1], * calcineurin [PP2B], and * protein-phosphatase-2A [PP2A] Phosphate activity leads to internalization of AMPARs and/or target CREB (→ dephosphorylation at Ser133)

Question 38

# Spike Timing-Dependent Plasticity (STDP) The general rule of STDP

Answer 38

If an input (EPSP) to a neuron occurs (on average) immediately before that neuron's output spike, then that input is potentiated (LTP) (→ “pre before post”). If an input (EPSP) occurs immediately after an output spike, then that input becomes weaker (LTD) (→ “post before pre”).

Question 39

At positive spike timings, large depolarization leads to

Answer 39

large Ca2+ influx through NMDARs, triggering LTP.

Question 40

Negative timings result in

Answer 40

moderate NMDAR Ca2+ influx and LTD → by the time of pairing some Mg2+ block has been restored.

Question 41

Depolarization from backpropagating APs reliefs

Answer 41

the voltage-dependent Mg2+ block of NMDARs

Question 42

STDP depends on

Answer 42

synapse location within the dendritic tree, as well as the active conductances in the dendrites

Question 43

The feedback signal during STDP is most likely mediated by

Answer 43

the backpropagating AP