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Séminaire - John Lisman Biochemical and structural synaptic processes that may underlie memory

Abstract :

CaMKII is an abundant synaptic protein, the activation of which by Ca entry through NMDARs is necessary for LTP and learning. We are investigating the hypothesis that persistently activated CaMKII, in association with NR2B, is a molecular complex responsible for the maintenance of LTP and memory. To test this hypothesis we conducted the critical “erasure test”. LTP was induced in CA1 pyramidal cells. After 30 minutes, we briefly applied a membrane permeant peptide (CN-peptide) that disrupts the complex of CaMKII with NR2B. 

This transient application produced a persistent erasure of saturated LTP. We found that LTP could then be reinduced by strong synaptic activity. These results suggest that the CaMKII/NMDAR complex has a key role in LTP maintenance. Using a FRET indicator of the CaMKII/NMDAR complex, we found that complex forms within five minutes after LTP induction.
The complex could thus be the Frey-Morris “tag”.  The role of this tag may be to organize proteins, some of which are synthesized after LTP induction, to produce the trans-synaptic synapse enlargement that underlies late LTP. Known binding reactions suggest several possible binding cascades that could underlie this structural process, but the actual mechanisms remain to be worked out. 

Does the CaMKII/NMDAR complex have the stability necessary to store memory for years, despite protein turnover? We have developed models of how the known autocatalytic reactions of CaMKII could produce the required stability. I will review several recent studies that lend credence to this model.