Molecular Substrates of Translation in Specific Neuronal Compartments During Memory Storage

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 DESCRIPTION (provided by applicant): Despite our understanding that consolidation of long-term memories (LTM) require new protein synthesis, the specific molecular substrates of translation are yet to be understood in detail. Recent studies have described abnormal protein synthesis in several neuropsychiatric disorders. Importantly, therapeutic potential of inhibition o translation in specific brain regions for treating Post-traumatic stress disorder (PTSD) have been described. Thus, better understanding of the molecular substrates of translation will help develop novel therapeutic treatments for disorders such as PTSD. The central hypothesis of this proposal derived from our own studies is that activation of translation of specific mRNAs in specific compartments of pre and postsynaptic neurons is required for establishing LTM. To test this hypothesis, we will identify molecular substrates of translation in specific neuronal compartments of pre and postsynaptic neurons by exploring the advantages of recently described tagging of polyribosomes (TRAP: Translating ribosome affinity purification) and well- characterized neural circuitry of gill-withdrawal reflex (GWR) of marine snail, Aplysia californica Specifically we will (1) isolate and characterize tagged polyribosomes immunoprecipitated from somatic and synaptic compartments of pre and post synaptic neurons of GWR that are exposed 5HT, a neurotransmitter important for learning in Aplysia and (2) characterize their function in memory storage by knockdown of specific candidates and electrophysiological analysis. We anticipate that these studies will provide the first ever description of molecular substrates of translation in specific pre and postsynaptic compartments of a neural circuitry and their temporal regulation during memory storage. Furthermore these studies will bring novel insights into dynamics of translation during LTM. These studies will have an important positive impact on our fundamental understanding of neural circuit function and memory storage and likely lead to identification of new targets for preventive and therapeutic interventions of memory disorders.