Role of synaptotagmins and neurexin ligands in homeostatic synaptic plasticity

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Center PI: Malenka, Robert, Principal Investigator: Chen, Lu/Südhof, Thomas (Project 3) Summary A long-standing question in the field of neuroscience is how plastic changes at synapses in a circuit enable learning, encode memory, and drive behavior. Compared to the progress made in relating Hebbian plasticity to animal learning, little is known about the behavioral significance of homeostatic synaptic plasticity. Based on the newly discovered signaling pathway involved in homeostatic synaptic plasticity – the synaptic retinoic acid pathway, and building on the progress made in the past years, this study aims to deepen our understanding of homeostatic synaptic plasticity by further exploring the involvement of postsynaptic exocytosis machineries and trans-synaptic adhesion molecules in homeostatic synaptic plasticity. Moreover, taking advantage of the known molecular components uniquely involved in the homeostatic synaptic plasticity, the study will probe in vivo functional significance of homeostatic plasticity by applying state-of-art genetic tools in animal behavioral studies. Through close collaboration with other projects of the Center, this project hopes to provide conceptual advancement to our understanding of homeostatic synaptic plasticity and retinoic acid signaling. Relevance The candidate molecules investigated in this project have been implicated in Autism spectrum disorders. Dissecting their involvement in homeostatic synaptic plasticity and RA signaling and examining the functional impact on animal learning when homeostatic plasticity is compromised will further our understanding of circuit maladaptation underpinning mental illnesses. PHS 398/2590 (Rev. 11/07) Page 1 Summary