Activity-induced Ca2+ signaling in perisynaptic Schwann cells is mediated by P2Y1 receptors and regulates muscle fatigue

Abstract

Perisynaptic glial cells respond to neural activity by increasing cytosolic levels of calcium, but the functional significance of this pathway is unclear. Terminal/persiynaptic Schwann cells (TPSCs) are a perisynaptic glial cell at the neuromuscular junction. Here, we provide genetic evidence that neural activity-induced intracellular calcium accumulation in neonatal TPSCs is mediated exclusively by P2Y₁ receptors. In P2ry1 mutant mice lacking these responses, postsynaptic, rather than presynaptic, function was altered in response to nerve stimulation. This impairment was correlated with a greater susceptibility to activity-induced muscle fatigue. Interestingly, fatigue in P2ry1 mutants was exacerbated by exposure to high potassium to a greater degree than in control mice. High potassium itself increased cytosolic levels of calcium in TPSCs, a response which was also reduced P2ry1 mutants. These results suggest that activity-induced calcium responses in perisynaptic glia at the NMJ regulate postsynaptic function and muscle fatigue by influencing the levels of perisynaptic potassium.