Microglial Transient Receptor Potential Melastatin 2 Deficiency Accelerates Seizure Development via Increasing AMPAR‐Mediated Neuronal Excitability

ABSTRACT Epilepsy is one of the most common neurological disorders, characterized by the enhancement of neural excitability from a neurocentric perspective. Emerging evidence indicates that microglia play a pivotal role in the pathogenesis of epilepsy through complex and various mechanisms that is still not fully understood. In this study, we demonstrate that the deficiency of transient receptor potential melastatin 2 (TRPM2) channel, a calcium‐permeable nonselective cation channel, significantly accelerates seizure development in multiple mouse seizure models, including MES‐ and pentylenetetrazole(PTZ)‐induced seizure model, intrahippocampal KA model, hippocampal kindling model, without affecting seizure susceptibility in initial acute seizure. Notably, it is the deficiency of TRPM2 specifically in microglia, rather than in CaMKIIα + excitatory neurons or PV + interneurons, that primarily responsible for seizure development. Moreover, microglial TRPM2 deficiency increases the excitability of hippocampal pyramidal neurons by enhancing the AMPAR‐mediated excitatory synaptic transmission independent of changes in the expression of inflammatory cytokines. These findings reveal a previously unrecognized, inflammation‐independent mechanism by which microglial instead of neuronal TRPM2 channel contributes to seizure development, highlighting microglial TRPM2 as a novel potential therapeutic target for epilepsy by specifically targeting microglial TRPM2 channel.