Microglia and its P2RY12 receptors regulate seizure severity

ABSTRACT Microglia have emerged as possible regulators of seizures with previous approaches employed being insufficiently selective of microglial-specific contributions. To more definitely determine microglial roles in seizure severity, we used the recently developed genetic microglial-deficient Csf1r ΔFIRE/ΔFIRE (FIRE KO) mouse model. In this model, mice lack microglia but retain brain border associated macrophages (BAMs). Using two experimental seizure paradigms with either a chemoconvulsant or electrical stimulation, we confirm that a microglial deficiency exacerbates seizures, reduces survival and facilitates the likelihood of developing spontaneous recurrent seizures, indicating that microglia constrain seizure activity across different seizure paradigms. To gain insights into molecular regulators of seizure severity under microglial regulation, we examined P2RY12 contributions and demonstrate that a loss of microglial P2RY12 increased seizure severity in both global and microglial-specific knockout mice indicating that microglia suppress seizure severity in chemoconvulsive models through P2RY12 signaling. During seizures, P2RY12-deficient microglia displayed altered process complexity, accompanied by increased neuronal activation and reduced inhibitory tone. These results link impaired microglial responses to heightened seizure susceptibility and network excitability. Together, our findings establish microglia as protective regulators of seizure activity and identify P2RY12 signaling as a critical mediator of microglia protective actions.