The Role of Ca^<2+>/Calmodulin-Dependent Protein Kinase II in Synaptic Plasticity.

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Synaptic plasticity in the central nervous system is thought to be important for the higher brain functions such as learning and memory, and the understanding of its fundamental mechanisms is one of the most important subjects of neuroscience today. The head investigator has been working on the molecular mechanisms of synaptic plasticity, with special emphasis on protein phosphorylation by Ca^<2+>/calmodulin-dependent protein kinase II (calmodulin kinase II,CaMKII). CaMKII is a multifunctional protein kinase especially enriched in the nervous system and has been implicatedin a variety of neuronal funcrions, but the precise mechanisms of its regulation and its role in living animals have not been clarified yet. In order to get an effective tool to understand the role of CaMKII in synaptic plasticity in vivo, the investigator first tried to search for antisense oligodeoxynucleotides (antisense ODN) against CaMKII which could sufficiently supress CaMKII expression in vivo. Despite the vigorous screening of antisense ODN using a neuroblastoma cell line overexpressing CaMKII in vitro, no effective candidate was found. As another tool, the investigator has succeeded in generating phosphorylation state-specific antibodies toward CaMKII which recognize CaMKII only after it is activated, i.e., autophosphorylated, and used these antibodies to understand the physiological regulation of CaMKII in response to acute neuronal excitation in vivo. The study showed that the activated, Autophosphorylated state of CaMKII was under dynamic and precise regulation in vivo, and proved these antibodies as powerful tools for the evaluation of the functional significance of CaMKII.Further application of these antibodies to understand the role of CaMKII in synaptic plasticity, as well as novel genetic approaches to regulate the expression of CaMKII in vivo, will be pursued by the investigator in the future.