The DEG/ENaC cation channel protein UNC-8 drives activity-dependent synapse removal in remodeling GABAergic neurons.

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

doi:10.7554/elife.14599

Abstract

Genetic programming and neural activity drive synaptic remodeling in developing neural circuits, but the molecular components that link these pathways are poorly understood. Here we show that the C. elegans Degenerin/Epithelial Sodium Channel (DEG/ENaC) protein, UNC-8, is transcriptionally controlled to function as a trigger in an activity-dependent mechanism that removes synapses in remodeling GABAergic neurons. UNC-8 cation channel activity promotes disassembly of presynaptic domains in DD type GABA neurons, but not in VD class GABA neurons where unc-8 expression is blocked by the COUP/TF transcription factor, UNC-55. We propose that the depolarizing effect of UNC-8-dependent sodium import elevates intracellular calcium in a positive feedback loop involving the voltage-gated calcium channel UNC-2 and the calcium-activated phosphatase TAX-6/calcineurin to initiate a caspase-dependent mechanism that disassembles the presynaptic apparatus. Thus, UNC-8 serves as a link between genetic and activity-dependent pathways that function together to promote the elimination of GABA synapses in remodeling neurons.

Highlights

Neural circuits are reorganized during development to produce a mature, functional nervous system
The resultant UNC-8::GFP fusion protein is functional in vivo and is expressed in Dorsal D (DD) neurons in the wild type and in Ventral D (VD) neurons in an unc-55 mutant
We detected strong UNC-8::GFP expression in adjacent ventral cord DA and DB cholinergic neurons as predicted by the selective degeneration of these cells in a mutant that encodes a constitutively active UNC-8 protein (Wang et al, 2013). These results suggest that the fosmid reporter likely includes gene regulatory regions that direct expression of the native UNC-8 protein (Figure 1—figure supplement 1A–C)

Summary

Introduction

Neural circuits are reorganized during development to produce a mature, functional nervous system. Circuit refinement involves both the elimination of specific synapses and the strengthening of others. These developmental changes in brain architecture are temporally coordinated with critical periods in which neuronal wiring can be shaped by activity. The establishment of binocular vision in the mammalian brain, for example, depends on visual input during a distinct developmental period in which the circuit is uniquely sensitive to neural activity.

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