Neural circuits are extensively refined during development as synapses are either created or destroyed to modify brain function. Neural activity is known to regulate these remodeling events but the molecular mechanisms that drive synaptic reorganization are poorly understood. This study tests the hypothesis that a member of the DEG/ENaC family of cation channels functions as a molecular link between neural activity and synaptic stability. This work exploits a synaptic remodeling event in the nematode C. elegans in which ventral synapses for the DD class of GABA neurons are re-located to new connections with dorsal muscles during larval development. This synaptic remodeling program is blocked by the UNC-55/COUP TF transcription factor in VD motor neurons, which normally synapse with ventral muscles. The Miller lab exploited this UNC-55 function in a cell-specific profiling strategy to identify 19 conserved genes with roles in synaptic remodeling. My work has now shown that one of these UNC-55 targets, the degenerin/epithelial sodium channel (DEG/ENaC), UNC-8, promotes synaptic remodeling in a mechanism that is activated by GABAergic signaling. This finding is important because DEG/ENaC proteins have been implicated in learning and memory but the molecular pathways that connect DEG/ENaC function to synaptic plasticity are largely unknown.
Specific Aim 1 tests the prediction that GABA neuron activity drives the remodeling process in a cell autonomous mechanism.
Specific Aim 2 tests the key hypothesis that UNC-8 localizes to the presynaptic regions of GABA neurons and functions in these cells to promote remodeling.
Specific Aim 3 tests the novel prediction that UNC-8 is activated by the transient depletion of extracellular calcium that accompanies GABA release and that this effect triggers disassembly of the presynaptic apparatus. The results of this study will provide a better understanding of the cellular mechanisms that connect circuit activity to dynamic events at the synapse. Additionally, this study may provide insights that reveal the biological basis of mental disorders that arise from dysfunctional synaptic connectivity.
Connections between neurons or synapses are actively reorganized during childhood to fine-tune the function of brain circuits. To understand the mechanism that controls this dynamic process, we are studying a simple example of synaptic remodeling in the nematode, C elegans. This study should reveal genes that function similarly in the vertebrate nervous system and may thus provide a deeper understanding of human brain disorders that arise from defects in synaptic connectivity.