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It is now well documented that certain patterns of the activity of neurons can lead to long-lasting changes in the strength of synapses. Furthermore, there are strong reasons to believe that these synaptic changes contribute to the brain modifications that underlie learning and memory.
Thus understanding the molecular basis of these changes is a path towards understanding the molecular basis of memory. We are using both theoretical and experimental methods to understand the underlying mechanisms.
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A core hypothesis is that the strength of synapses is controlled by the Ca/calmodulin protein kinase II known to be concentrated in the postsynaptic density of synapses. Theoretical work suggests that positive feedback autophosphorylation of this kinase could produce a molecular switch and be the perpetuating reaction underlying synaptic memory. Such switches would turn on during LTP.
Furthermore, according to this model, the neural stimulation that produces synaptic weakening does so by activating a phosphatase cascade that resets the kinase switch. To experimentally test this and other hypotheses concerning the biochemical basis of synaptic modification, we have developed a method for perfusing a patch pipette during whole cell recording in the hippocampal slice.  | | Click to Enlarge |
This allows us to add enzymes or enzyme inhibitors to the neuron at defined times before or after the induction of LTP or LTD. One major effort has been to test the CaM-Kinase hypothesis described above. Our current work does not support this hypothesis, but variants, perhaps involving redundant protein kinases, remain to be explored. In addition, a major effort has been made to understand the role of cAMP and PKA in the synaptic modification process.
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