Miller-Fleming, Tyne W. et al. (2015) International Worm Meeting "The degenerin/epithelial sodium channel protein UNC-8 drives activity-dependent synaptic remodeling in GABAergic neurons."

Manning, Laura, Miller III, David M., Richmond, Janet E., Hori, Sayaka, Matthewman, Cristina, Gornet, Megan, Petersen, Sarah C., Mitani, Shohei, Bianchi, Laura, Miller-Fleming, Tyne W.

[International Worm Meeting, 2015]

Developing neural circuits undergo extensive refinement mediated by transcriptional mechanisms and environmental cues; however, the specific molecules that mediate these interactions are uncharacterized. The Degenerin/Epithelial Sodium Channel (DEG/ENaC) family of proteins has been shown to play a role in mammalian and invertebrate plasticity and here, we identify the DEG/ENaC protein UNC-8 as a critical regulator of GABAergic synaptic remodeling in C. elegans. We see that UNC-8 is required in GABA neurons for the proper removal of synapses in a transcriptionally controlled and activity-dependent remodeling mechanism. UNC-8 drives GABA neuron remodeling in parallel to the Iroquois family homeodomain transcription factor, IRX-1. Additionally, UNC-8 cation channel function is necessary to dismantle presynaptic domains. We find that UNC-8 functions in a common genetic pathway with neurotransmitter release. Our results suggest that UNC-8 functions as a sensor of GABAergic activity to promote synapse disassembly, thereby serving as a potential link between genetic mechanisms and neurotransmission in the developing nervous system. .

Miller, Tyne W et al. (2013) International Worm Meeting "The degenerin family ion channel UNC-8 promotes activity-dependent remodeling of GABAergic synapses in C. elegans."

Wang, Ying, Miller, Tyne W, Bianchi, Laura, Petersen, Sarah C, Miller, David M, Hori, Sayaka, Richmond, Janet E, Matthewman, Cristina, Gornet, Megan E, Mitani, Shohei, Lu, Han

[International Worm Meeting, 2013]

Synaptic networks are extensively remodeled in the developing brain by mechanisms that require neural activity. Members of the DEG/ENaC (Degenerin/Epithelial sodium channel) family are known to modulate plasticity in the mammalian brain, but the molecular events that regulate this effect are poorly defined. Here we describe an activity-dependent mechanism in which the DEG/ENaC protein, UNC-8, promotes synaptic remodeling in C. elegans. GABAergic Dorsal D (DD) motor neurons reverse polarity by relocating synapses from ventral to dorsal muscles in the first larval stage. This pathway is blocked by the UNC-55/COUP-TF transcription factor in Ventral D (VD) GABAergic neurons, which ectopically remodel in an unc-55 mutant. We exploited this mutant phenotype in a cell-specific profiling strategy to identify UNC-55-regulated transcripts. This approach revealed fifty UNC-55 targets that are required for GABA neuron remodeling, including UNC-8. We find that UNC-8 functions in DD neurons where it is localized near ventral DD synapses. Our results show that UNC-8 is required for removing ventral synapses in a mechanism that depends on GABA. A necessary role for neurotransmitter release is also suggested by our finding that a voltage-gated calcium channel subunit, UNC-2, promotes remodeling. In vitro reconstitution of an UNC-8 channel results in robust cation transport activity that is strongly inhibited by extracellular calcium. The negative effect of calcium on UNC-8 function is consistent with a model in which depletion of extracellular calcium by UNC-2 at active GABAergic synapses effectively relieves the calcium block and thereby induces UNC-8 activation. Our results support a model in which UNC-8 functions as an activity sensor in GABAergic DD motor neurons to trigger the deconstruction of ventral synapses, thus promoting the remodeling process.