Investigating the Role of cnb-1 and chpf-1 in GABA DD Motor Neuron Remodeling and Synapse Maintenance

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Project Summary During development of the human brain, synaptic connections undergo intensive rewiring in order to form mature circuits. Disruption of developmental remodeling in humans is linked to neurological disorders such as schizophrenia and autism spectrum disorders. The goal of this project is to identify conserved mechanisms that direct synapse remodeling. The ease of genetics, couple with the simpler organization and invariant architecture of invertebrate nervous systems offer strong advantages for studies of neuronal remodeling. My work focuses on the remodeling of GABAergic dorsal D-class (DD) motor neurons in the nemaode Caenorhabditis elegans. Prior studies have largely focused on the remodeling of presynaptic terminals. In contrast, my preliminary work has focused on understanding mechanisms that direct the elimination of postsynaptic receptors during remodeling. post-synaptic domain. The Francis lab previously demonstrated that the homeodomain transcription factor dve-1 is required for synapse elimination in GABA neurons. My work focuses on two putative DVE-1 targets, the calcineurin-like EF-hand protein CHP1/chpf-1 and the regulatory subunit of CalciNeurin PPP3R1/cnb-1, that were shown to be downregulated in dve-1 mutants. My preliminary studies suggest that mutation of either cnb-1 or chpf-1 disrupt synapse elimination during remodeling. My proposed work will determine the functional requirement and site of action for cnb-1, and identify the contribution of calcineurin phosphatase and proteasomal function to synapse elimination (Aim 1). In Aim 2, I will define how chpf-1 contributes to synapse elimination and maintenance. In Aim 3, I will identify additional potential targets of dve-1 in the remodeling pathway by using neuron-specific RNA-seq. My proposed work will advance our understanding of remodeling and the mechanisms of regulation, potentially providing targets for future exploration.