An α7 nicotinic and GABA B receptor-mediated pathway controls acetylcholine release in the tripartite neuromuscular junction

Terminal Schwann cells (TSCs) are capable of regulating acetylcholine (ACh) release at the neuromuscular junction (NMJ). We have identified GABA as a gliotransmitter at mouse NMJs. When ACh activates α7 nicotinic ACh receptor (nAChRs) on TSCs, GABA is released and activates GABAB receptors on the nerve terminal that subsequently reduce ACh release. Indeed, specific deletion of the α7 nAChR in TSCs or inhibition of the metabotropic GABAB receptor prevents the reduction in the quantal content of the end-plate potential induced by cholinesterase inhibitors. The α7/GABAB receptor-mediated pathway is activated when ACh that escapes from collagen Q (ColQ) anchored AChE in the synaptic cleft and from PRiMA-anchored butyrylcholinesterase on the TSC activates α7 nAChRs on the TSC. Consequently, prolonged tetanic stimulation of isolated muscle activates the α7/GABAB receptor pathway, which reduces post-tetanic ACh release. When AChE levels are low in neonatal mice, the α7/GABAB receptor-mediated pathway decreases ACh release and reduces ex vivo muscle fatigue. For ColQ-deficient mice where AChE is not clustered, the decrease in AСh release following activation of this pathway contributes to mouse fatigue in vivo.