Glial Synaptobrevin mediates peripheral nerve insulation, neural metabolic supply, and is required for motor function

Abstract

Peripheral nerves contain sensory and motor neuron axons coated by glial cells whose interplay ensures function, but molecular details are lacking. SNARE‐proteins mediate the exchange and secretion of cargo by fusing vesicles with target organelles, but how glial SNAREs contribute to peripheral nerve function is largely unknown. We, here, identify non‐neuronal Synaptobrevin (Syb) as the essential vesicular SNARE in Drosophila peripheral glia to insulate and metabolically supply neurons. We show that tetanus neurotoxin light chain (TeNT‐LC), which potently inhibits SNARE‐mediated exocytosis from neurons, also impairs peripheral nerve function when selectively expressed in glia, causing nerve disintegration, defective axonal transport, tetanic muscle hyperactivity, impaired locomotion, and lethality. While TeNT‐LC disrupts neural function by cleaving neuronal Synaptobrevin (nSyb), it targets non‐neuronal Synaptobrevin (Syb) in glia, which it cleaves at low rates: Glial knockdown of Syb (but not nSyb) phenocopied glial TeNT‐LC expression whose effects were reverted by a TeNT‐LC‐insensitive Syb mutant. We link Syb‐necessity to two distinct glial subtypes: Impairing Syb function in subperineurial glia disrupted nerve morphology, axonal transport, and locomotion, likely, because nerve‐isolating septate junctions (SJs) could not form as essential SJ components (like the cell adhesion protein Neurexin‐IV) were mistargeted. Interference with Syb in axon‐encircling wrapping glia left nerve morphology and locomotion intact but impaired axonal transport, likely because neural metabolic supply was disrupted due to the mistargeting of metabolite shuffling monocarboxylate transporters. Our study identifies crucial roles of Syb in various glial subtypes to ensure glial‐glial and glial‐neural interplay needed for proper nerve function, animal motility, and survival.

Advances in the study of axon–associated vesicles

“…Disruption of the binding of this region will largely affect the entire process of exocytosis. However, the detailed physiological significance and functional role of this interaction require further research ( Toonen et al, 2005 ; Böhme et al, 2021 ).…”