Molecular genetics of synaptic remodeling

A half century of research has determined that the Immunoglobulin Superfamily protein, Neural Cell Adhesion Molecule (NCAM), regulates key events in neural development including synaptic assembly and function, neurite outgrowth and cell migration. Our work in C. elegans has now revealed a new role of NCAM in synaptic remodeling. Moreover, our discovery that human NCAM is functional in C. elegans argues that NCAM may also regulate synaptic remodeling in the brain. Developing neural circuits are actively remodeled as synapses are created in new locations and dismantled in others. Synaptic plasticity has been observed throughout animal phylogeny which suggests that the underlying pathways are conserved and thus can be investigated in simple model organisms that are amenable to experimental analysis. During early larval development, DD- class GABAergic neurons in C. elegans execute a dramatic remodeling program in which the presynaptic apparatus exchanges locations with postsynaptic components within the DD neuronal process. We have previously shown that the DEG/ENaC cation channel protein, UNC-8, activates a Ca+2-dependent pathway that promotes recycling of presynaptic components to new locations in remodeling DD neurons. We have now used single cell RNAseq (scRNA-seq) to identify additional effectors of DD remodeling. We have shown that NCAM- 1, and its binding partner, the Immunoglobulin super family (IgSF) protein RIG-3, are upregulated in developing DD neurons. We hypothesize that the NCAM-1/RIG-3 protein adhesion complex functions in parallel to UNC- 8/DEG/ENaC to promote presynaptic disassembly and recycling. Aim 1 uses biochemical and structural analysis to establish the molecular basis of NCAM-1 binding to RIG-3 and experiments in vivo to validate the synaptic remodeling roles of specific NCAM-1/RIG-3 protein interactions. This goal is important because NCAM has been implicated in learning and memory but mechanisms that link NCAM to synaptic remodeling are largely unknown. Aim 2 tests the hypothesis that the NCAM-1/RIG-3 complex functions with the F-BAR protein TOCA-1 in an actin-dependent mechanism that recycles presynaptic components for assembly at new locations. This aim is important because TOCA-1 is a conserved effector of branched actin assembly that is highly expressed in the mammalian brain. We will also test the hypothesis that highly conserved binding sites for key components of the actin cytoskeleton in the NCAM-1 intracellular domain also contribute to NCAM-1- dependent synaptic remodeling. Together, these approaches offer a powerful opportunity to delineate intricate molecular pathways that link neural activity to genetic programming in the execution of a synaptic remodeling mechanism. The strong conservation of remodeling components in C. elegans including NCAM argues that this work is likely to reveal fundamental mechanisms that regulate synaptic plasticity in the mammalian brain. Project Number: 1R01NS144899-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: DAVID MILLER (+2 co-PIs) | Institution: VANDERBILT UNIVERSITY, Nashville, TN | Award Amount: $614,306 | Activity Code: R01 | Study Section: Neuronal Communications Study Section[NC] View on NIH RePORTER: https://reporter.nih.gov/project-details/11368183