Our study first reveals that pyroptosis of astrocytes is induced during the pathogenesis of the CMS model and demonstrates an unexpectedly pivotal role of NLRP3/Casp-1/GSDMD–mediated pyroptosis in CMS model–induced behavioral changes, as well as astrocytic loss in the hippocampus. Here, NLRP3 is linked to congenital myasthenic syndrome.