LTD Flashcards
Barnes et al 1994
Could you get more LTP if you re-tetanise at the synapse? What is the extent to which you can repeatedly induce LTP
After repeated tetanic bursts (in vivo also) you can max out the amount of LTP you see in a pathway. Frankly, you cant get anymore.
But this posed a problem, if LTP is a neural basis of memory and you can create memories that last a lifetime and can generat enew ones throughout the lifetime, then if the LTP saturated, then where is thecapacity fo the network to store new memories? This question supposes that one synapse participates in any more than one memory. There is no indication that this is true.
There is a stimulating electrode and recording electrodes in amny of the synapses, then you have saturation after repeated stimuli
Turrigiano (1999)
What is the alternative for LTP? There are two - one is input specific and the other is not - the one that is not is homeostatic plasticity
Homeostatic plasticity was first described in crayfish -> this was picked up by Turrigiano and explored if this was true in mammals.
Take a population of synapses and upregulate or downregulate ther performance i.e. EPSPs. But not in one specific synapse in an input specific way, but across teh entire population.
The starting weight of any synapse in the network may be increased or decreased but the absolute wweight will stay constant compared to the neighbouring synapse.
How do we induce this?
Manipulate the network using pharmacological systems such a TTX which is a sodium channel blocker. If you block the sodium channels then you have a block in the spiking activity and therefore the activity of the network decreases and therefore causes the network to become more active in response? EPSPs become larger across the network but relative proportions stay same.
If you prevent the inhibitory tone, by giving a GABA inhibitor, then you could have increased activity in the network, recurrent excitation, which has an effect of dampening down the EPSPs.
Increasingly there is evidence that this scaling can be acheived in vivo rather than using the pharmacological tricks.
Barrioneuvo et al. (1980)
De-potentiation follows LTP induction
The other possibility to Homeostatic plasticity is LTD but it is input specific unlike the HP. This means if you wanted to solve the gain control problem, which was explored to see if LTD was a thing or not, then you would need to turn the gain down on the very same synapses which were turned up in the first place.
It took a long time to generate an experimental protocol which would model the synaptic response.
Dudek, Bear – found the LTD protocol?
They used a protocol which was take a brian slice and apply a stimulus at 1Hz rather than HFS, and provide 900 of these stimuli. This is not very physiologically relevant but this is enough to prove the principle.
Barrionuevo et al 1980
- You can depress the synaptic response – in an input specific way
o You can remove potentiation at the sites of previous potentiation = depotentiation
You can depress synaptic response and depress it in a long lasting way and achieve it in an input specific way. You can remove potentiation at sites where there was previous potentiation - depotentiation (not quite same as LTD but used together)
Dudek & Bear (1992)
NMDA receptor dependent LTD
Dudek described the original LTD and Dudek and Bear also described the underlying mechanism (basic) which was the cause for LTD. With the 1Hz protocol with an NMDAR antagonist APV, we see that there is LTD is induced and is gone back to baseline after APV is applied.
Mulkey & Malenka (1992)
NMDA-R dependent LTD is triggered by Ca2+ influx
Wont the LTP and LTD both clash?
Bolshakov & Siegelbaum (1994) Science
Oliet et al. (1997) Neuron
mGluR (1 & 5) dependent LTD
You can block the NMDARs and still be able to induce LTD by stimulating the mGluR pathway via the IP3 which is a potassium mobilising agent. This causes a calcium flux which is partnered with the depolarisation of the spine which causes a calcium flow through the channels.
Cerebellar LTD?
Others have also repeated this experiment
Otani & Connor (1998)
mGluRs are required for LTD induction
Experiment using MCPG which is an antagonist of the MGluR and also by using a calcium chelator BAPTA - both blocks the LTD induction
This provides similareveidence as Lynch for the LTP that calcium is necessary
Gerdeman et al. (2002)
endoCannaBinnoid LTD
First found in the Striatum and layer V visual cortex
But other people have also found the others.
KO animals with no receptor - then there is no ability for the cells to have LTP induction without the CB1 receptor.
LTP expression
Benke et al. (1998) Nature
Derkach et al. (1999) PNAS
AMPA-R phosphorylation and de-phosphorlation
Something must link the calcium to the receptor which mediates the current - this is CaMKII
Benke showed that AMPAR conductance can be increased due to LTP induction (We know that this is not the whoel story)
LTD expression
Lee et al. (1998) Neuron
Banke et al (2000) J. Neurosci
AMPA-R phosphorylation and de-phosphorlation
Something must link the calcium to the receptor which mediates the current - this is CaMKII
Following Benke showed that AMPAR conductance can be increased due to LTP induction, if LTD dephosphorylates at key sites, then the enhancement would revert back to what it was before the potentiation.
The performance of the receptors does seem to change in repsonse to the phosphorylation or potentiaiton
Hey-Kyuang Lee et al. (2003)
Lack of NMDA receptor dependent LTD and reduced LTP in double phosphomutant mice (lack the 2 major GluR1 phosphorylation sites)
You can get rid of LTD if you have key phosphate groups modified such that they cant be phsophorylated. In other words, if you have key sites which are compromised by not being in the molecule then there is no prospect of dephosphorylating at all
The capacity of LTD is vanished because there is no potentiation??
It can be shown that the capacity to produce LTD can be lost
Mulkey, Herron & Malenka (1993)
Protein phosphatase inhibitors block induction of LTD (Inhibition of PP1)
Inhibit the enzymes which are phosphatases - which cut of the phosphate that is dephosphorylate.
Okadaic acid is a generic phosphotase inhibitor - if it is applied to a brain slice, and attempt to induce LTD then you cannot - when you remove the ability to remove phosphate gorups then the ability to have LTD also goes
Mulkey et al. (1994)
Calcineurin is a Ca2+ /Cam dependent phosphatase
The calcium rise in the cell is important for the induction of LTD - and we have to link this rise in calcium to some enzymatic activity just like the alpha CaMKII in LTP
Calcineurin is a phosphatase - it is calcium sensitive and its target is a calcium calmodulin. This is an important paper in the LTD field
Zakharenko et al. (2002)
Presynaptic LTD
FM- de-staining is decreased after mGluR LTD induction
Synaptic transmission rate has decreased with LTD
Errington et al 1995 - but see Malenka and Bear 2004
LTD cannot be induced in adult hippocampus in vivo
While LTP studies has started in intact animals with Lomo and Bliss and then into the slices, while LTD went the other way.
But the review by Malenka and Bear explores why we may be failing to do so
