Activity-dependent regulation of CaMKII and synaptic plasticity

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Abstract Memories of salient events in our lives are part of what makes us individuals. CaMKII has been shown to be required in both vertebrates and invertebrates for short-term (STM) and long-term memory (LTM). CaMKII protein is enriched at synapses, and is synthesized locally in response to activity patterns that lead to LTM formation. Both of these features require specific sequences present in the distal untranslated part of the CaMKII mRNA. In spite of extensive work on local translation of CaMKII, several fundamental questions remain unanswered: Is there a requirement for somatic factors in local translation? We will disrupt the connection between the cell body and the synapse to test whether transport of somatic material to the synapse is required for activity-stimulated local synthesis of CaMKII. How is the information specifying local translation encoded in mRNA? Using transgenes encoding fluorescent reporters and real-time assays of new protein synthesis, we will determine what sequences are required for CaMKII synaptic localization and activity-dependent translation. What are the cellular components that read this information? We will do a bioinformatically-driven candidate gene screen in parallel with RNA affinity purification to identify proteins that regulate basal and plasticity-stimulated CaMKII accumulation. How does disruption of local translation of CaMKII affect LTM? We will use conditional genome editing to remove mRNA sequences that specify local translation or to replace them with specific mutants. We will determine which cells in the adult learning circuit use this information during LTM formation. This project utilizes cutting-edge genetic, cell biological and optical methods to address the molecular basis of a phylogenetically-conserved mechanism of plasticity in a way that will further our understanding of complex behaviors.