Synaptic plasticity Flashcards
Forms of plasticity distinguished by:
Duration
* Direction of effect
* Source of induction
Site of expression
Duration
- Short term – msec to minutes
- Long term – hours to days, weeks, or longer
- Direction of effect
enhancement
- depression
Source of induction
- homosynaptic –
intrinsic to synapse - heterosynaptic –
third neuron involved
Site of expression
- 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.)
Synaptic Facilitation
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.
Synaptic facilitation are a result of
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
Synaptic depression
Reduction in synaptic strength during successive action potentials
- Depletion of readily releasable vesicles
- inactivation of release sites, and
- inactivation of calcium channels.
Synaptic depression results from
progressive depletion of vesicle pool (and to lesser extent inactivation of
release sites, and inactivation of calcium channels)
Rate of depression depends on
amount of transmitter released (the more is released initially, the less
is available on subsequent APs)
lowering Ca2+ reduces
the probability of release and slows rate of depression
Both Augmentation and Potentiation
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
Augmentation
rises and falls over a few seconds
possible target: Munc-13 (helps with priming)
post-tetanic potentiation (PTP)
asts over a time scale of tens of seconds to minutes
possible target: synapsin (facilitates trafficking from reserve pool)
During repetitive synaptic activity
different forms of short-term
plasticity
interact
Sensitization results from
activation of
the serotonergic modulatory
interneuron, which increases the EPSP at
the motor neuron → heterosynaptic
Sensitization (short term)
5-HT (via a metabotropic receptor) activates Adenylyl-cyclase, which in turn increases cAMP, and then PKA.
PKA has 2 effects in Sensitization
Closes K+ channels, leading to
broader spikes and more Ca2+ influx
→ more transmitter release
- PKA also directly increases the
release of neurotransmitter
Sensitization (long term – weeks)
after repeated pairings, PKA also
phosphorylate
s CREB (transcription factor)
Sensitization (long term – weeks
CREB stimulates
ubiquitin hydrolase
→ keeps PKA persistently active
(degrades PKA’s regulatory subunit)
Sensitization (long term – weeks)
C/EBP →
regulates activity of other
(unknown) genes that lead to structural
changes, i.e. growth of new synapses
Hebb’s theory of synaptic plasticity
“Cells that fire together, wire together”
postulates that when one
neuron drives the activity of another neuron, the connection
between these neurons is potentiated
Characteristics of (NMDAR-dependent) LTP
Input (synapse) specificity
Associativity
Cooperativity:
State-dependence
Input (synapse) specificity:
LTP is restricted to active synapse
Associativity
coincident activation of a weak pathway together with a strongly activated
pathway will lead to LTP in the weak pathway.
Cooperativity
coincident activation of several weak pathways may also act cooperatively
to provide sufficient depolarization
State-dependence
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
presynaptic LTP is characterized by
enhanced transmitter release
2 possible mechanisms of Presynaptic LTP:
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)
While induction entails the transient activation of CaMKII
and PKC, maintenance of the early phase of LTP is
characterized by their persistent activation.
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
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.
Silent synapses
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.
Activation of silent synapses is a proposed mechanism
(and proof-of-concept) for
rapid increases in synaptic efficacy
Calmodulin activates CaMKII, which
phosphorylates and inserts
AMPARs
into the postsynaptic membrane
→ unsilencing of silent synapse
Long-term synaptic depression - LTD
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
Long-term synaptic depression results mainly from a
decrease in postsynaptic AMPA receptor density
LTD results from activation of
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)
Spike Timing-Dependent Plasticity (STDP)
The general rule of STDP
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”).
At positive spike timings, large depolarization leads to
large Ca2+ influx through NMDARs, triggering LTP.
Negative timings result in
moderate NMDAR Ca2+ influx and LTD
→ by the time of pairing some Mg2+ block has been restored.
Depolarization from backpropagating APs reliefs
the
voltage-dependent Mg2+ block of NMDARs
STDP depends on
synapse location within the dendritic tree, as
well as the active conductances in the dendrites
The feedback signal during STDP is most likely mediated by
the backpropagating AP
