Developing neural circuits are actively remodeled as synapses are created in new locations and dismantled in others. These dynamic changes are driven by the combined effects of genetic programs and neural activity that together shape the architecture and function of mature circuits. 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. Here we propose to use the nematode, C. elegans, to define a development program that remodels the synaptic architecture of a GABAergic circuit. During early larval development, DD-class GABAergic neurons undergo a dramatic remodeling program in which the presynaptic apparatus exchanges locations with postsynaptic components within the DD neuronal process. To reveal the mechanism of this effect, we are investigating the functional roles of ~20 conserved genes that we have determined are transcriptionally regulated to drive GABA neuron remodeling. Our work has shown that two of these targets, the DEG/ENaC cation channel protein, UNC-8, and ARX-5/p21, a conserved component of the Arp2/3 complex, function together in an activity-dependent mechanism that dismantles the presynaptic domain.
Aim 1 tests the hypothesis that UNC-8 cation transport elevates intracellular calcium to drive presynaptic disassembly and that this effect is regulated by calcium- dependent phosphorylation. This goal is important because members of the DEG/ENaC protein family have been implicated in learning and memory but the mechanism that links DEG/ENaC function to synaptic plasticity is poorly understood.
Aim 2 tests the hypothesis that the UNC-8 function triggers an actin-dependent endocytic mechanism that recycles presynaptic components for reassembly at new locations. These experiments derive from our surprising discovery that a key functional protein of the Arp2/3 actin-branching complex is transcriptionally regulated to effect synapse removal and that newly identified components of an endocytic recycling pathway are involved. 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. Moreover, the conservation of C. elegans remodeling components in mammals argues that this work is likely to reveal fundamental mechanisms that regulate synaptic plasticity in the human brain.

Public Health Relevance

Normal brain development is defined by the active reorganization of connections or synapses between neurons. To identify genes that regulate these complex events, we are studying a synaptic remodeling program in the nematode, C elegans, an organism with a simple, well-defined nervous system and powerful tools for genetic analysis. The results of this work should reveal genes with similar roles in the vertebrate nervous system and thereby provide important clues to the biological basis of human diseases that arise from dysregulated mechanisms of synaptic remodeling.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Lavaute, Timothy M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Vanderbilt University Medical Center
Anatomy/Cell Biology
Schools of Medicine
United States
Zip Code
Matthewman, Cristina; Johnson, Christina K; Miller 3rd, David M et al. (2018) Functional features of the ""finger"" domain of the DEG/ENaC channels MEC-4 and UNC-8. Am J Physiol Cell Physiol 315:C155-C163
Matthewman, Cristina; Miller-Fleming, Tyne W; Miller Rd, David M et al. (2016) Ca2+ permeability and Na+ conductance in cellular toxicity caused by hyperactive DEG/ENaC channels. Am J Physiol Cell Physiol 311:C920-C930
Miller-Fleming, Tyne W; Petersen, Sarah C; Manning, Laura et al. (2016) The DEG/ENaC cation channel protein UNC-8 drives activity-dependent synapse removal in remodeling GABAergic neurons. Elife 5:
He, Siwei; Philbrook, Alison; McWhirter, Rebecca et al. (2015) Transcriptional Control of Synaptic Remodeling through Regulated Expression of an Immunoglobulin Superfamily Protein. Curr Biol 25:2541-8
Wang, Ying; Matthewman, Cristina; Han, Lu et al. (2013) Neurotoxic unc-8 mutants encode constitutively active DEG/ENaC channels that are blocked by divalent cations. J Gen Physiol 142:157-69