Tetanus neurotoxin sensitive SNARE-mediated glial signaling limits motoneuronal excitability

Peripheral nerves contain motoneuron axons coated by glial cells, which essentially contribute to function but cellular reactions remain poorly understood. We here identify non-neuronal Synaptobrevin (Syb) as the essential vesicular SNARE in glia to insulate and metabolically supply Drosophila motoneurons. Interfering with Syb-functionality by glial knockdown, or glial expression of tetanus neurotoxin light chain (TeNT-LC) caused motonerve disintegration, blocked axonal transport, induced tetanic muscle hyperactivity and caused lethal paralysis. Surprisingly, not the established TeNT-LC-target, neuronal Synaptobrevin (nSyb), is the relevant SNARE, but non-neuronal Synaptobrevin (Syb): 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 glia: to establish nerve insulating septate junctions in subperineurial glia and to integrate monocarboxylate transporters along the nerve in wrapping glia for motoneuronal metabolic supply. Our study identifies crucial roles of Syb in glial subtypes for nerve function and pathology, animal motility and survival.