Molecular analysis of neural circuit excitation and inhibition

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Developmental remodeling of circuit connectivity is a key process in shaping the mature organization of neural circuits in the brain, optimizing their connectivity in order to perform specific functions. Remodeling is triggered by both environmental stimuli and intrinsic genetic mechanisms, and deficits in remodeling processes are thought to be a primary factor underlying altered patterns of connectivity observed in a variety of neurodevelopmental and neuropsychiatric disorders. Despite the clear importance of these developmental processes for normal brain physiology and health, there are major gaps in our understanding of the cellular and molecular mechanisms that regulate neural circuit remodeling. Studies of genetic models have proven to be extremely fruitful for identifying fundamental mechanisms underlying neural circuit development and function. Our previous studies have pioneered new approaches for elucidating mechanisms for the specification of synaptic connectivity in a genetically tractable model, the nematode Caenorhabditis elegans. During the previous funding period, we demonstrated the remodeling of postsynaptic specializations located on GABAergic neurons in the C. elegans motor circuit, and showed that the formation of new synapses during remodeling is associated with the outgrowth of previously uncharacterized spines on GABAergic dendrites. Moreover, we uncovered a novel mechanism required for spine outgrowth and synapse assembly that depends on the synaptic organizer neurexin. These findings demonstrate the strength of this system for identifying key genes with conserved roles in shaping neural circuit connectivity and place us in a strong position for a deep investigation of in vivo molecular mechanisms. Indeed, in preliminary studies supporting this application we have identified the homeodomain transcription factor DVE-1, a homolog of mammalian chromatin organizers SATB1/2, as a key hub for regulation of synapse elimination during remodeling of the motor circuit. In Aim 1 of this proposal we investigate a novel transcriptional network controlling synapse disassembly and elimination. In Aim 2, we explore cellular and molecular mechanisms underlying the assembly of new synapses during circuit remodeling, focusing on the role of the conserved synaptic organizer neurexin. We expect that our studies of this experimentally tractable circuit in the worm will have a major impact on our understanding of the molecular processes involved in circuit remodeling. Additionally, we anticipate that the novel molecules and signaling mechanism we identify will be excellent candidates for therapeutic intervention to treat neurodevelopmental disorders involving disruptions in circuit connectivity.