Short-term and Long-term Plasticity Flashcards
direct gating
the binding of transmitter to the receptor on the extracellular aspect of the protein directly opens the ion channel embedded in the cell membrane
indirect gating
G protein-coupled receptors activate GTP-binding proteins that engage a second-messenger cascade or act directly on ion channels
phosphorylation of GluR4 subunit by PKA promotes:
increased GluR4-containing AMPAR trafficking to post-synaptic density
Rp-cAMP
competitive inhibitor of cAMP and therefore PKA activation
what are the different types of G-protein cascades?
Gs, Gi/o, Gq
Gs-protein
stimulates adenylyl cyclase, increases cAMP and PKA activity
Gi/o-protein
inhibits adenylyl cyclase, decreases cAMP and PKA activity
Gq-protein
generates IP3 to trigger Ca2+ release from internal stores and activates PKC via PLC and DAG
plasticity
the capacity of the neural activity generated by an experience to modify neural circuit function and thereby modify subsequent thoughts, feelings, and behaviour
synaptic plasticity
activity-dependent modification of the strength or efficacy of synaptic transmission at preexisting synapses
how to increase short-term plasticity?
- short-term facilitation/paired-pulse facilitation (presynaptic Ca2+)
- post-tetanic potentiation (presynaptic Ca2+)
- presynaptic augmentation
how to decrease short-term plasticity
- short term depression (vesicle depletion)
- presynaptic metabotropic receptors
- Ca2+ channel inactivation
- postsynaptic receptor desensitization
short-term presynaptic facilitation/paired-pulse facilitation
- usually occurs at synapses where release probability is initially low
- second stimulation (with little time delay) = presynaptic Ca2+ accumulates causing greater amounts of neurotransmitter release and greater EPSP
- facilitation becomes less apparent as time interval between first and second presynaptic stimulation increases because Ca2+ is no longer accumulating
short-term presynaptic depression/paired-pulse depression
- depression usually occurs at synapses where release probability is initially high
- inactivation of voltage-dependent sodium or calcium channels, or transient depletion of the release-ready pool of vesicles docked at the presynaptic terminal
post-tetanic potentiation
residual Ca2+ in the presynaptic terminal caused by high frequency firing leads to a short-term enhancement of synaptic transmission
synapses with a low initial probability of release function as:
high-pass filters, they will facilitation during high-frequency action potential bursts but will not transmit low-frequency bursts with the same efficacy
synapses with a high initial probability of release function as:
low-pass filters, they will depress during high-frequency bursts but will reliably relay low-frequency activity
the voltage change in the neuron is usually a result of:
summated voltage changes from synapses at dendrites
what defines a strong connection between two neurons?
voltage change in postsynaptic neuron is large in response to presynaptic neuron action potential
LTP
strengthening of synapses, long lasting enhancement in signal transmission resulting from stimulating neurons synchronously
LTD
weakening of synapses, long lasting attenuation in signal transmission
ionotropic glutamate receptors
AMPA, Kainate, NMDA
metabotropic glutamate receptors
mGluR1-8
AMPA receptors
permeable to Na+ and K+, influx of Na+ depolarizes the cell
NMDA receptor (resting membrane potential)
- requires d-serine or glycine as a cofactor
- magnesium block at negative voltages (does not significantly contribute to postsynaptic depolarization)
NMDA receptor (when the cell is depolarized and Mg2+ block is removed)
- requires d-serine or glycine as a cofactor
- permeable to Ca2+, Na+ and K+
- opens and closes slowly
a large influx of calcium (from NMDA receptor activation) results in activation of:
calcium dependent kinases (e.g. CaMKII) which leads to enhanced receptor exocytosis and stabilization of AMPA receptors to the postsynaptic site (more AMPA to bind to, more current to flow through, increased postsynaptic potential in response to glutamate)
-active calcium dependent kinases can also phosphorylate AMPA receptors, increasing their expression or making them more permeable
the majority of AMPA receptors incorporated into synapses during LTP are from:
lateral diffusion of spine surface receptors containing GluR1 and GluR2 AMPA receptor subunits.
fusion of recycling endosomes (from intracellular pools to postsynaptic membrane) containing AMPA receptors is mediated by:
Rab11a
moderate influx of calcium
- does not cross threshold required to activate kinases
- activates calcium-dependent protein phosphatases (e.g. calcineurin) and protein phosphatases 1 (PP1) which increases endocytosis of AMPA
- cause of LTD
binding of Ca2+ calmodulin to CaMKII results in:
autophosphorylation of all the subunits and leads to persistent activation, if the Ca2+ signal is not strong enough, phosphatases inactivate the kinase
conventional method for achieving LTP
high-frequency tetanic stimulation (100Hz for 1s)
conventional method for achieving LTD
low-frequency stimulation (5Hz for 3 min given twice with a 3 min interval
presynaptic stimulation paired with post synaptic depolarization (LTP)
short bursts of high frequency stimulation combined with postsynaptic depolarization to 0mV (voltage clamp)
presynaptic stimulation paired with post synaptic depolarization (LTD)
low frequency stimulation with postsynaptic depolarization to -40mV (voltage clamp)
a large Ca2+ influx leads to:
exocytosis of GluR1 and GluR2 containing AMPA receptors, these then diffuse laterally to the postsynaptic spine (PSD) and are trapped there
APV or AP5
competitive NMDA receptor antagonist
what is the critical window of time in which synaptic plasticity can occur
20ms before and after an action potential
spike-time dependent plasticity
additional method for altering synaptic plasticity
- presynaptic cell fires <20ms before postsynaptic neuron = LTP
- postsynaptic cell fires an action potential 20-50ms before the presynaptic cell = LTD
what does spike-time dependent plasticity occur (LTP)?
if presynaptic cell fire a second action potential <20ms after the first, glutamate binds to AMPAR on postsynaptic synapse causing depolarization and removal of magnesium block from NMDAR. glutamate binds to NMDA causing Ca2+ influx. Then, back propagating AP from postsynaptic neuron contributes to depolarization at the post synaptic density, amplifying effects
what does spike-time dependent plasticity occur (LTD)?
if postsynaptic cell fires an action potential 20-50ms before the presynaptic cell, postsynaptic cell becomes depolarized and then begins to repolarize. when the presynaptic cell fires an action potential (releases glutamate), glutamate reaches postsynaptic cell while it is repolarizing and at a lower hyperpolarized voltage, so fewer NMDA receptors are available and results in only a moderate influx of Ca2+
STDP
the timing of the back-propagating action potential relative to the EPSP determines the sign and magnitude of synaptic modification
the majority of AMPA receptors incorporated into synapses during LTP are from:
lateral diffusion of spine surface receptors containing GluR1 and GluR2 AMPA receptor subunits
what provides a scaffolding for AMPA receptor incorporation?
Ca2+ calmodulin dependent kinase II (CaMKII) - holds them in the post-synaptic density after LTP has occurred
fEPSP
field excitatory post-synaptic potential
population spike
may be recorded after a fEPSP in an extracellular recording, corresponds to the population of cells firing action potentials (spiking)
extracellular recordings
assess a population of synapses
intracellular recordings
assess synapses on a single neuron
how do you measure NMDA current only (at +40mV)?
measure from 50-100ms after onset of the peak/after stimulation, at this time, there should be no contribution from AMPARs
silent synapse
a synapse in which an excitatory postsynaptic current (EPSC) is absent at the resting membrane potential but becomes apparent on depolarization (low intensity stimulation does not reveal AMPA currents, NMDA currents are present if cell is depolarized)
the conversion of “silent” to “active” synapses account for:
LTP at immature synapses
synapse unsilencing occurs when:
coordinated pre- and post-synaptic activity (e.g. paired LTP induction protocol) results in activation of NMDARs and the subsequent recruitment of AMPARs to the postsynaptic membrane
-this is a mechanism of LTP expression
can silent synapses mediate neurotransmission?
NO, because they lack AMPARs, cannot depolarize in response to glutamate
immature synapses
possess only NMDA receptors and lack AMPA receptors on the post-synaptic density (i.e. silent synapses)
structural changes of the synapse accompanying LTP
size of the post-synaptic density and dendritic spine increase, this also increases the size of the presynaptic active zone
the size of the post-synaptic density is proportional to:
the number of AMPARs present
structural changes of the synapse accompanying LTD
spine head shrinkage (decrease in post-synaptic density)
the size and stability of dendritic processes relates to:
the strength of the connection/synapse
small and dynamic dendritic processes =
ill-formed or newly formed weak synapses
large and static dendritic processes =
previously formed, strong synapses
experience dependent structural changes to dendritic spines
unilateral retinal lesions do not change overall spine density in the visual cortex, but there is a dramatic loss of previously persistent spine and greater gains in new persistent spines after lesion compared to controls
-demonstrates potential for plasticity by spine growth and retraction
n =
number of synapses
p =
probability of release
q =
quantal size, or the amplitude of the postsynaptic response to the glutamate from one vesicle
presynaptic LTP
triggered by high-frequency tetanic stimulation, which causes a large activity-dependent increase in Ca2+ concentration within presynaptic axon terminals, this activates a calcium/calmodulin-dependent adenylyl cyclase which increases presynaptic cAMP which activates PKA and phosphorylates critical presynaptic substrates to cause a long-lasting enhancement in transmitter release (e.g. mossy fibre synapses)
mossy fibre synapses
the synapses between the axons of dentate gyrus granule cells (i.e. mossy fibres) and the proximal apical dendrites of CA3 pyramidal cells
endocannabinoid-mediated LTD
occurs at excitatory synapses onto medium spiny neurons in the striatum
endocannabinoids
retrograde messengers that are released by postsynaptic cells in response to strong depolarization and/or activation of GPCR, function to transiently inhibit transmitter release at either excitatory or inhibitory synapses via activation of presynaptic CB1 receptors
metaplasticity
refers to a higher-order form of synaptic plasticity in which synaptic activity, which by itself does not directly affect synaptic efficacy, leads to a persistent change in the direction or magnitude of subsequent activity-dependent synaptic plasticity
(after the first event, the synapse is primed such that a subsequent event leads to changes in plasticity)
how many therapeutic drugs exert their effects using mechanisms similar to those that generate LTP and LTD?
drugs may have significant effects on the phosphorylation of AMPAR subunits, thus affecting their surface expression
