Microglia and its P2RY12 receptors regulate seizure severity.

Microglia are possible regulators of seizures but previous employed approaches are insufficiently selective of microglial-specific manipulations. To more definitely determine microglial roles in seizure severity, we used the microglial-deficient Csf1r ΔFIRE/ΔFIRE mouse model where mice lack microglia but retain brain border-associated macrophages. Using two experimental paradigms, we confirm that a microglial deficiency exacerbates seizures and facilitates the likelihood of developing spontaneous recurrent seizures, indicating that microglia constrain seizure activity. To gain insights into microglial molecular regulators of seizure severity, we examined P2RY12 contributions and demonstrate that a loss of P2RY12 increased seizure severity in both global and microglial-specific knockout mice indicating that microglia suppress seizure severity. 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, we establish microglia and P2RY12 signaling as protective regulators of seizure activity.