LTP/LTD/STDP Flashcards
Hebb’s postulate? (and when)
When an axon of cell A is near enough to excite a cell B and repeatedly or persistently take part in firing it, some growth process/metablic change takes place in one/both cells such that A’s efficiency, as one of the cells firing B, is increased
How can this requirement for correlated pre- and postsynaptic synaptic activity be interpreted?
Requirement for convergent and synchronous activity (presynaptic)
What did Terje Lomo observe (and when)? (+ref)
Persistent increase in synaptic strength after pairing pre- and postsynaptic activity (1966) - Bliss & Lomo, 1973
What did early studies of EC-GC synapses show identify? (+ref)
Features of a Hebb synapse - ability for long-term increases/decreases in synaptic strength (Levy and Stewart. 1979)
What else does the Hebb synapse require?
Coactivity of a number of presynaptic elements to induce such changes
Cooperativity?
A weak input, in which only a few excitatory synapses were tetanize, failed to induce LTP, whereas a strong input reliably induced LTP
What was only seen in the tetanized pathway? (and what does this demonstrate)
A strong input reliably induced LTP, but only in the tetanized pathway (“input specificity”)
Associativity?
Simultaneous activation of two seperate inputs, one of which is weak and fails to undergo LTP on its own, exhibits robust LTP when tetanized together with a strong input
What did Levy and Steward (1983) find?
Changes in synaptic efficacy (EC-DG) dependent on the temporal order of the input stimuli
What did potentiation/depression result from? What was this the first evidence for?
When the LFS preceded HFS by less than 20 ms (and reverse led to weakening) - first evidence for sensitivity of synaptic modification to relative timing of pre- and postsynaptic spikes
What did Markram verify (and when)?
The significance of the relative timing + defined a critical window for the coincidence detection (10s of milliseconds) - 1997
What does the temporal requirement for STDP depend on?
Preparation, brain area, cell types and dendritic location - classical form = excitatory glutamatergic synapses in HPC
What produces maximal synaptic modification?
Small differences between pre- and postsynaptic spikes produce maximal synaptic modification (no plasticity observed when difference is too large)
Relative order determines LTP/LTD: ref?
Abbot and Nelson, 2000
What is the requirement of causality further reinforced by?
The exponential decay in the amount of LTP, which restricts the potentiation to the spikes arriving within the temporal window during which a neuron is able to integrate inputs
What does the fact that STDP restricts plasticity to active synapses exemplify?
Input-specificity of Hebbian plasticity
How does STPD expand Hebb’s original hypothesis?
Cells that fire together can wire together or unwire, depending on the timing between cells A and B
What does STDP also address?
More temporally sensitive computation tasks, while adding stability to neural networks
What does the Hebbian model assume, and what does this lead to?
That LTP/LTD occur independently at each synapse, which can lead to instability in the form of excessively low or high firing rates,
How does STDP provide a source of stability for recurrent networks without leading to runaway excitation? (+ ref)
By enforcing a specific temporal order, synapses from the presynaptic to postysnaptic neuron are strengthened while those in the opposite order will be weakened (Gilson et al., 2010)
The NMDAR is believed to act as a coincidence detector… (+ref)
….allowing the influx of Ca2+ following the presynaptic release of glutamate and coincident postsynaptic depolarisation that results in the removal of the MG2+ block (Mayer et al., 1984)
What does the cooperativity threshold of LTP arise from? (+ explanation for why weak stimulus doesn’t produce LTP)
From the need for depolarisation to reduce the level of block (weak stimuli activating only a few afferent fibres fail to induce LTP because the resulting level of depolarisation does not produce adequate reduction in the block)
When does depolarisation spread between neighbouring synapses?
Many fibres activated in synchrony by a strong stimulus (enhances unblocking of NMDARs)
Calcium hypothesis? (+ref)
Depending on stimulation, two distinct types of Ca2+ signals can arise - separate downstream pathways (Artola and Singer, 1993)
What does the intracellular rise in Ca2+ after HFS promote?
Activation of CaMKII followed by LTP induction
What does LFS result in? (+ref)
More gradual rise in Ca2+ that leads to the recruitment of phosphatase, e.g. PP1 and calcineurin (Yang et al., 1999)
Proposed mechanism for LTP? (+ref) [residue!]
Phosphorylation of Ser831 of GluA1 by CaMKII, enahancement of their transmission + strengthening of synapse (Malinow and Malenka, 2002)
What else is involved in synaptic modification? (+ref)
Postsynaptic TrkB receptors which can increase NMDAR conductance to upregulate Ca2+ influx (Figurov et al., 1996)
What else is proposed to be triggered by the influx of calcium ions? (+ref)
Downstream signalling pathways, such as the positive feedback loop following mTOR-dependent translation of the neurotrophin BDNF which stimulates presynaptic transmitter release, while postsynaptically interacting with TrkBRs to increase phosphorylation of NMDARs (Hao et al., 2018)
What does this lead to (BDNF, TrkB..)? (+ref)
Increase in the open probability while facilitating synaptic clustering and AMPAR upregulation (Caldeira et al., 2007)
What have APs been shown to do once initiated? (+ref)
Spread through the dendritic tree in a retrograde manner (Stuart et al. 1997)
What does a bAP represent and what is it believed to serve?
Represents the integrated sum of all (active) presynaptic inputs onto a neuron and is believed to serve as a specialised associative signal that can facilitate the removal of the Mg2+ block + activity-depednent influx of Ca2+
What does the bAP promote? (+ref)
Modification of dendritic synapses that contributed to the inititiation of the AP (Markram et al., 1997)
What other mechanism could explain the narrow window for coincidence detection?
Kinetics of Mg2+ unblock
What does the voltage-dependence associated with the Mg2+ unblock mean?
Synaptic currents are prolonged when the membrane is depolarised, which can facilitate LTP through the enhancement of NMDAR conductance
What does the time-dependence of the unblock lead to? (+ref)
Sharpening of the window for coincidence detection and induction of STDP (Kampa et al., 2004)
Where does another influence on the window for LTP induction arise from?
Interactions between the bAP and EPSP, which can promote changes in active dendritic conductances
What happens to A-type K+ channels expressed in the distal dendrites in the HPC? (+ref)
Inactivated by EPSP which locally depolarises the membrane, boosting subsequent bAPs arriving within a time window of tens of milliseconds (Magee and Johnston, 1997)
What does the inactivation of A-type K+ channels do?
Facilitates the associative element of LTP
What follows from the activation of voltage-gated Na+ channels in the distal dendrites?
Similar effect - enhancing the bAP and increasing influx of Ca2+ through VDCC
What regulates the magnitude of LTP being induced at active synapses? (+ref)
The manipulation of dendritic conductances through non-linear interactions between the bAP and EPSP, when the EPSP precedes the bAP (Bi and Poo, 1998)
What can the window for LTD induction be explained in terms of?
The interaction between the bAP
What does the coincidence of an EPSP with the after-hyperpolarization phase of the bAP result in? (+ref)
A relatively small influx of Ca2+ (as seen with LFS), resulting in LTD (Caporale and Dan, 2008)
What is another mechanism (bAP/LTD)? (+ref)
Inactivation of NMDA channles following the influx of Ca2+ through VDCCs, causing sublinear summation of Ca2+ signalling (Bi and Poo, 1998)
What do mGluRs, in combination with Ca2+ influx through VDCCs lead to?
Activation of PLC, which can act as a signal for eCB synthesis
What did blockade of CB1 receptors lead to? (+ref)
Blockade of CB1Rs by AM251 prevented LTD, indicating that retrograde eCB signaling via CB1Rs is required for LTD, through the presynaptic inhibition of neurotransmitter release (Bender, 2006)
What does blocking the binding of BDNF to TrkBRs lead to?
Reduction in the synaptic response to HFS as well as the magnitude of adult hippocampal LTP
What does blocking of binding of BDNF to TrkBRs suggest? (+ref)
BDNF may regulate hippocampal LTP by enhancing the synaptic response to HFS (Figurov et al., 1996)
