Lecture 4: LTP, LTD and behaviour
How much AMPA do we have on the membrane?
You do not have much AMPA in the brain at start, not quite enough to activate the neurons by themselves. Thus, NMDA is the key receptor in LTP, but it requires co-activation of pre and post- synaptic neurons, which happens by Hebbian rule. The co-activation develops gradually by creating synapses that are individually strong (individually as effective).
What does Ca2+ do when it travels through NMDA?
It does more than depolarisation of the post-synaptic neuron. It activates permanent events on the membrane, e.g. activate protein kinases which introduce more phosphate for AMPA to increase in number and efficiency.
Problem with LTP, however, is that it ends up potentiating everything, thus each potentiation needs to be balanced with depression, i.e. if you need to increase some synapses, you need to decrease
efficiency of other synapses. BCM (Bienenstock, Cooper & Munro) theory is an extension of Hebb’s theory which accounts for bidirectional (up and down) regulation of synaptic strength.
EPSP = strength (effectiveness) of synapse CA1 = hippocampus neuron
LTP
Potentiate synapse for long-term, but it does not make that particular neuron more excitatory. It needs high frequency - 1000 Hz tetanus.
LTD
This happens if stimulus has a very low frequency (1 Hz tetanus). But it does not make that particular neuron more inhibitory.
Hence, both LTP and LTD depends on how much activation is put in NMDA, i.e. concentration of Ca2+determines what postsynaptic neuron does. Low [Ca2+] = LTD, high [Ca2+] = LTP.
So what exactly happens in LTD?
Small concentration of Ca2+leads to activation of protein phosphotase instead of kinase (like in LTP).
This protein removes phosphate ions, thus reduces AMPA number and effectiveness, resulting in long-term depression.
How do these AMPA fit in the membrane then?
AMPA in postsynaptic membrane are continually being added and removed even in the absence of synaptic activity. However, synaptic transmission will remain stable as long as one receptor is added whenever one receptor is removed, this equilibrium is disturbed by LTP and LTD. The membrane acts as an egg carton, i.e. if there is a space for AMPA to fit in the membrane, like an empty space in the carton, the AMPA fits in there.
Are the molecules involved in LTP and LTD also involved in learning and memory?
Injection of NMDA-receptor blocker into hippocampus: rats in Morris water maze were unable to locate the escape platform.
Tonegawa et al. knocked out (deleted) the gene for one subunit of protein kinase (involved in LTP): rats showed deficits in both LTP and memory
LIMITATION - developing without a gene may have caused the abnormality of failing to complete certain tasks, loss of LTP/memory may be a secondary consequence.
Tonegawa et al. restricted the deletion of NMDA receptors to CA1 by switching off kinase starting at 3weeks of age within the context for a short period of time: rats showed a deficit in LTP and water maze performance