Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motoneurons (MNs) in a motor-unit (MU)-dependent manner. Glial dysfunction contributes to numerous aspects of the disease. At the neuromuscular junction (NMJ), early alterations in perisynaptic Schwann cell (PSC), glial cells at this synapse, may impact their ability to regulate NMJ stability and repair. Indeed, muscarinic receptors (mAChRs) regulate the repair phenotype of PSCs and are overactivated at disease-resistant NMJs [soleus muscle (SOL)] in SOD1G37R mice. However, it remains unknown whether this is the case at disease-vulnerable NMJs and whether it translates into an impairment of PSC-dependent repair mechanisms. We used SOL and sternomastoid (STM) muscles from SOD1G37R mice and performed Ca2+-imaging to monitor PSC activity and used immunohistochemistry to analyze their repair and phagocytic properties. We show that PSC mAChR-dependent activity was transiently increased at disease-vulnerable NMJs (STM muscle). Fur...