LTD Flashcards
• Barrioneuvo et al (1980):
Got a pathway that is normalises 100%, classical KLTP is induced using HFS, and different protocol low frequency (1Hz for 100 secs) Schaffer collaterals. Rats stimulating electrode in stratum radiatum near the junction of CA1 and CA3 subfeilds of dorsal hippocampus. Extracellular recordings
o In 12.5% if cases produced a persistent depression of control response
o In 77.7% of cases LFS significantly reduced potentiated responses
o LFS produced a persistent depression of previously potentiated responses in the hippocampus
o Interesting aspect that depression was that it was detected primarily after LTP had been introduced→ may indicate that the depression is brought about by action on the cellular mechanisms which produce potentiation. Alternatively a relationship may exist between the size of synaptic response and degree of stimulation-induced depression
o So it appears LFS will significantly and persistently reduce LTP effect → a mechanism to offset?
o – still seeing depression in ‘niave’ synapses so suggests not just depotentiation
• Dudek and Bear (1992):
AP5 applied to brain slice. Inducing LTD with 900 pulses delivered at 1Hz. Schaffer collateral projection to area CA1 in rat hippocampal slices were stimulated electrically at frequencies ranging from 0.5-50Hz. Population EPSPs
o There is a NMDAR dependant variant of LTD Could be prevented by application of AP5
o 900 pulses at 1-3Hz consistently yielded a depression of CA1 pEPSPs that persisted for greater than one hour
o LTD was specific to conditioned input, ruling out generalised changes
o Depressed synapses continued to support LTP in response to HFS
o Data suggest that synaptic depression can be triggered by prolonged NMDAR activation that is below the threshold for inducing synaptic potentiations
• Mulkey and Malenka (1992):
Used Ca2+ chelating compound dialysed into the extracellular space. (Have a nice embedded control cause they’ve performed extracellular field recordings on cells that have the cells where the chelator is present to demonstrate that neuron behaves in different way) Repetitive low freq 1hz for induction of LTD in CA1 pyramidal cells. Application of 10-30s period of stimulation can also produce LTD
o NMDAR-dependant LTD is triggered by Ca2+ influx
o LTD was synapse specific, saturable, and required activation of post-synaptic NMDARs.
o Loading CA1 cells with the Ca2+ chelator BAPTA prevented LTD.
o Following LTD, synaptic strength could be increased to maximal level indicating that LTD is reversible and not due to deterioration of individual synapses
o Induction of homosynaptic LTD therefore requires an NMDA receptor dependant change in post-synaptic Ca2+ which may be distinct form that required for LTP
o LTD was blocked by buffering postsynaptic Ca2+ by strong hyperpolarisation during the induction protocol but unaffected by the L-VGCC antagonist nifedipine
o Magnitude of Ca2+ entry through NMDA may determine the direction of synaptic change (would been there is a way of that biochemical processes activated differentially according to the magnitude of the Ca2+ change.)→ potentially encoded in relative activity of CaMKII and phosphatase 1
• Bienenstock et al (1982):
Mathematical model BCM rule→r efers to the theory of synaptic modifications to account for experiments measuring the selectivity of neurons. Unlike traditional methods of stabilizing Hebbian learning, this “sliding threshold” provides a mechanism for incoming patterns, as opposed to converging afferents, to compete
o Their BCM rule fixes the positive feedback loop problem with a sliding threshold which is controlled by the output of the post-synaptic firing so the higher the FR, the higher the threshold which increases the range of depression,
o Physical theory of learning in visual cortex → proposed a sliding threshold for LTP and LTD induction (synaptic plasticity is stabilised by a dynamic adaptation o the tie-averaged postsynaptic activity)
o Assumes that active synapses undergo LTD or LTP depending on the level of post-synaptic response → assumed the threshold is not fixed but varoes as a function of the previous activity of post-synaptic cortical neurons. Threshold increases after a period of increased activity→ promoting depression and decreases after period of decreased activity promoting potentiation
• Wang and Wagner (1999):
CA1 field EPSPs obtained from rat hippocampal slices. Monitor synaptic responses before and after conditioning stimuli (3-100Hz) of the Shaffer collateral inputs. Extracellular recording electrode. HFS priming. Priming enhances the depression observed
o Substantial rightward shift (>5 fold) in the frequency threshold between LTD and LTP was observed <1 hr after priming
o Change in threshold occurred at both primed and unprimed synaptic pathways
o provide new support for the existence of a rapid, heterosynaptic, experience-dependent mechanism that is capable of modifying the synaptic plasticity phenomena
o -Only looked in one direction
• Oliet et al (1997):
CA1 hippocampal pyramidal cells in juvenile rats.
o AIDA (antagonist of group 1 mGluRs -1 and 5) blocks mGluR-LTD. PKC inhibitory peptide blocked mGluR LTD but not NMDAR-LTD
o Phosphatase inhibitor blocked NMDAR-LTD
o Used DAP5 to block NMDAR and Blocked mGluR with MCP
o NMDAR and mGluR dependant LTD
o Both are pathway specific and require membrane depolarisation and a rise in postsynaptic Ca2+
o mGluR LTD require activation of T-type Ca2+ channels, group 1 mGluRs and PKC
o NMDAR LTD require protein phosphatase activity
o Indicate that mechanistically distinct forms of synaptic plasticity and coexist
• Otani and Connor (1998):
FURA-2 imaging. LFS to Schaffer collateral CA1 neurons synapses in adult rat hippocampus→ Suggests that LTD induction in adult hippocampus by prolonged LFS depend on both a rapid influx through Voltage-sensitive channels and synaptic stimulation of mGluRs
o Generate Ca2+ in the inductive pathway shown by the BAPTA blocking LTD
o NMDA independent, postsynaptic Ca2+ dependant depression of synaptic strength
o Ca2+ changes were insensitive mGluR antagonist (MCPG) but MCPG blocked LTD → potentially rapid influx of Ca2+ is co-operative with more prolonged episode of synaptic activation of mGluRs
o Postsynaptic hyperpolarisation blocked Ca2+ changes and attenuated LTD
o LTD induction blocked by postsynaptic presence of PKC inhibitor
• Gerdeman et al (2002)
Striatum and layer V visual cortex. Using genetic KO of receptors, specifically CB1 receptors. Whole cell patch camp electrophysiology in brain slices of CB1-/- mice. HFS for induction of striatal LTD
o LTD is abolished→ Seems that in some pathways and circumstances the receptors that are required for induction of LTD now use other receptor classes eCB receptors.
o LTD was facilitated by blocking cellular endocannabinoid uptake
o Show that induction of LTD is dependant on activation of CB1 receptor
o Shown that AEA can activate presynaptic inhibition of transmission when loaded into postsynaptic neurons, consistent with a retrograde messenger role for the endocannabinoid
• Lee et al (2003):
Mice with knock in mutations in GluR1 site → phosphomutant mice (prevent phosphorylation of these sites). Whole cell recordings
o Lack of NMDAR-dependant LTD and reduced LTP
o Find that these mice lack NMDAR-dependant (usedAP5) LTD and show reduced LTP in the CA1 region of the hippocampus. Had problems in retention and not learning of a spatial memory task with MWM
o Mice show deficits in LTD and LTP and have memory deficits in spatial learning tasks
o Indicate that phosphorylation of GluR1 is critical for LTD ad LTP expression and retention of memories (did not retain after 8-24houors)
o Suggests that this phosphorylation is critical for LTD expression and important for stability of LTP→ potentially Internalisation of the AMPAR are regulated by phosphorylation. Phosphorylation may stabilise in the membrane (hence stabilisation of LTP) and dephosphorylation for internalisation .
• Mulkey et al (1993):
): Okadaic acid (protein phosphatase inhibitor) CA1 of rat hippocampus Extracellular and whole cell recording techniques (Schaffer collaterals → CA1)
o Extracellular application of Okadaic acid or calyculin A (inhibitors of PP1 and PP2A) blocks induction of LTD
o Application of caluyculin A after LTD induction reversed the synaptic depression, suggesting that phosphatase activity is required for the maintenance of LTP
o Seems that effect seems to be through blocking PP1
o - PP1 is not Ca2+ dependant in any way and yet LTD is→ what is the Ca2+ independent link that means that PP1 inhibition is significant
• Mulkey et al (1994)
Calcineurin (a Ca2+/CaM-dependant phosphatase)→ calcineurin inhibitors and different forms of inhibitor 1 loaded into postsynaptic cells
o Results indicate that a signalling pathway in which calcineurin dephosphorylates and inactivates inhibitor 1 → This in turn increased PP1 activity and contributes to the generation of LTD
o (Inhibitor 1 when phosphorylated inhibits PP1 activity)
o Calcineurin inhibitors blocked LTD induction and no discernible effects on LTP. Direct loading of CA1 pyramidal cells, blocked LTD.
o Loaded cells with I1 → LTD was completely blocked (when loaded with unphosphorylated I1 then had no effect)
o Model Ca2+ influx through NMDAR channels → activation of calcineurin by CaM → this dephosphorylates I1→ which thus results in activation of PP1
o - Not looked at effect of I1 on PP1
• Kameyama et al (1998):
Hippocampal slices
o Show that dephosphorylation by PKA substrate may be crucial for LTD expression
o PKA activators inhibited both AMPAR dephosphorylation and LTD.
o Injection of cAMP analog into the postsynaptic neurons prevented LTD induction and reversed previously established homosynaptic LTD without effecting baseline synaptic transmission
o Infusing PKA inhibitor into the post synaptic cells produced synaptic depression that occluded homosynaptic LTD
o Suggest that dephosphorylation of PKA site on AMPAR may be a mechanism for NMDAR – dependent homeostatic LTD expression
• Zakharenko et al (2012):
): Quantal optical analysis. FM143 (fluorescent marker of presynaptic activity) CA2 and CA1 region
o FM de-staining is decreased after mGluR LTP induction
o MPEP application during the induction protocol not only blocked LTD of EPSP but also completely blocked the change in FM de staining.
o AP5 had no effect on LTD or alter FM
o Significant decrease in rate of FM1-43 release in response to synaptic stimulation following induction of mGluR-LTD → provides most direct evidence for altered presynaptic function
• Errington et al (1995):
n vivo studies. Stimulation at 1-5Hz in schaffer collaterals to CA1. Looked at LTD or depotentiation in awake adult rat and in anaesthetised rat
o Unable to generate LTD but were able to generate de-potentiation
o In DG no evidence for depotentiation or LTD in awake or anaetsthetised animal. In CA1 area also no evidence of adult rats.
o Only in CA1 of very young rats (10-11days) was clear evidence for LTD and depotentiation obtained (could only perform in anaesthetised)
o Experiments suggest that repetitive LFS evokes a developmentally regulated form of activity dependant depression in the hippocampus is limited to the specific pathway in young animals
o Thus seems that LTD and depotentiation in CA1 hippocampus area slice are not effective in vivo (only when very young anaesthetised animals
o Why the difference in effects between in vitro and in vivo effects
o So suggests that taking a niave synapse and taking below baseline may not always be possible
o Surprising as would have thought generating LTD in vivo is possible. Been demonstrated that LTD can be generated in vivo in cortical areas but the hippocampus proves to be a vivacious in this regard. → may simply be because the right protocol has not yet been found
• Burette et al (1997):
Field potentials elicited by stimulation of CA1 of the ventral hippocampus were recorded in the prelimbic area of the prefrontal cortex. Examined the ability of several patterns of LFS stimulation to induce LTD and depotentiation in hippocampo-PFC pathway in vivo
o No evidence that LTD in prefrontal cortex
o LFS with single pulse or paired pulses couldn’t but two pulse burst protocol selectively produced rapid reversal of LTP (depotentiation) in this patway
o Repeated trains failed to decrease the PFC response below original unpotentiated level demonstrate the existence of depotentiated mechanisms that is capable of exerting powerful control over ongoing or recently induced synaptic plasticity in hippocampocortical connections in vivo
o Is there regional differences?
o TBP stimulation selectively induces depotentiation but not LTD in the hippocampo-PFC pathway in vivo
o Suggest that low frequency activation in itself is not sufficient for producing effect but repeated stimulation with TPBs at short interpulse interval is required
o Potentially requirement for enhanced NMDAR activation
