Synaptic plasticity is thought to be a basis of learning and memory of the brain. Signaling mechanisms underlying synaptic and behavioral plasticity have been extensively studied with the aid of pharmacological and genetic manipulation of signaling. However, it has been difficult to assess the spatiotemporal aspects of signaling activity particularly. The goal of this proposal is to develop a new technique based on genetically encoded light- inducible kinase inhibitors to resolve the spatiotemporal dynamics of signaling required for synaptic and behavioral plasticity in vivo. Our preliminary data using a newly- developed photo-inducible CaMKII inhibitor demonstrates that ~60 s of CaMKII activity is sufficient to induce structural plasticity of dendritic spines.
We aim to 1) develop photo- inducible inhibitors for kinases including CaMKII, PKC and PKA, 2) determine the timing of kinase activity required for synaptic plasticity in slices, and 3) identify the spatiotemporal window of kinase activity required for learning-related dendritic spine turnover in vivo and animal?s performance improvement after learning. The new tool will provide new insights into the action of kinases in vivo during synaptic and behavioral plasticity.
Synaptic plasticity, learning and memory are regulated by signaling mediated by kinases. Many forms of learning disabilities and other mental diseases are caused by abnormal kinase signaling. Our proposed research will develop new tools to analyze kinase activity in neurons during synaptic and behavioral plasticity. This will improve our knowledge of the biochemical events that underlie synaptic plasticity, learning and memory, and will hopefully provide significant insights into the molecular mechanisms underlying mental disorders.
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