Neural circuits and their dynamic alteration control behavior. Neural circuits are composed of billions of neurons that communicate at synapses via the process of synaptic transmission, whereby neurotransmitters are released and bind to their respective receptors. Synaptic transmission can be persistently modified by neuronal activity in a process termed synaptic plasticity, acting to dynamically modulate animal behavior. Conversely, dysregulation of synaptic plasticity contributes to various psychiatric and cognitive disorders including autism, schizophrenia, mental retardation, and addiction. Therefore, proper synaptic plasticity is crucial for human health. Among various types of synaptic plasticity, NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) has been extensively studied. In this form of LTP, NMDAR activation increases synaptic AMPA receptor (AMPAR) activity through activation of CaMKII that drives AMPARs from a reserve pool to synapses. Though more than 100 molecules have been implicated in LTP, the direct cellular machinery remains unclear. Recently, we identified TARP?-8 as a critical CaMKII substrate for LTP. In this propsal, we aim to reveal the fundamental mechanisms of AMPAR potentiation during synaptic plasticity. Successful completion of this proposal will provide fundamental mechanistic insights into LTP and its roles in controlling animal behavior. Considering synaptic plasticity as a general model to mediate dynamic brain function, elucidating the molecular mechanisms underlying the control of synaptic plasticity will enable us to identify putative molecular targets for drugs to alleviate psychiatric and cognitive disorders. Moreover, the identification of the critical molecules that control synaptic plasticity directly is a chief neurobiological goal.
Dysregulation of synaptic plasticity and synaptic transmission contributes to various psychiatric and cognitive disorders including autism, schizophrenia, mental retardation, and addiction. Therefore, proper synaptic plasticity is crucial for human health. And elucidating the molecular mechanisms underlying the control of synaptic plasticity will enable us to identify putative molecular targets for drugs to alleviate psychiatric and cognitive disorders.
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