Investigating the Role of cnb-1 and chpf-1 in GABA DD Motor Neuron Remodeling and Synapse Maintenance
During development of the human brain, neurons are forming a mature neural circuit, which requires major rewiring of synaptic connections. Developmental remodeling helps the brain integrate rewired connections, which when disrupted is linked to neurological disorders such as schizophrenia and autism spectrum disorder. The goal of this project is to identify mechanisms regulating the highly conserved process of synapse remodeling. I will be using the simple model system Caenorhabditis elegans because it undergoes a striking example of remodeling in GABAergic dorsal D-class (DD) motor neurons. Prior work on synapse remodeling has largely focused on the presynaptic side, while my preliminary work has focused on the post-synaptic domain. The Francis lab has identified dve-1 to act as a transcription factor of remodeling, specifically synapse elimination. Through bulk RNA-sequencing (RNA-seq) I have identified 2 downregulated targets of dve-1, the calcineurin-like EF-hand protein CHP1/chpf-1 and the regulatory subunit of CalciNeurin, PPP3R1/cnb-1. Preliminary data has shown a defect of synapse remodeling in both cnb-1 and chpf-1. Additionally, I will determine the functional requirement and site of action for cnb-1 and identify the contribution of calcineurin phosphatase function and the proteasome to the effect of cnb-1 on synapse remodeling. In aim 2, I will further characterize the role of cnb-1 in both synapse elimination and maintenance, while also identifying the effect of calcium binding on synapse remodeling. In aim 3 I will identify potential targets of dve-1 in the remodeling pathway by using neuron-specific RNA-seq. My proposed work will advance the understanding of remodeling and the mechanisms of regulation, potentially providing targets for future exploration.
