Type I interferon signaling promotes kainic acid-induced seizures through mTOR activation

Abstract

Epilepsy is a chronic neurological disorder characterized by recurrent seizures, yet the role of type I interferon (IFN) signaling in seizure pathogenesis remains elusive. In this study, we show that deficiency of type I IFN signaling reduces seizure severity in a kainic acid-induced mouse model. Ifnar1(-/-) mice exhibited significantly lower seizure scores at multiple time points (e.g., U = 88.5, p = 0.0078 at 110 min), along with decreased neuronal excitability and microglial activation in these mice in response to kainic acid stimulation. Conversely, intracerebroventricular injection of IFN-beta exacerbated kainic acid-induced seizure severity. In vitro calcium imaging demonstrated that IFN-beta treatment enhanced neuronal excitability, although no significant difference in basal neuronal excitability were observed between wild-type and Ifnar1(-/-) neurons. Additionally, Ifnar1(-/-) mice showed reduced activation of the mammalian target of rapamycin (mTOR) pathway in the brain following kainic acid administration-a pathway known to contribute to epileptogenesis. Consistent with this finding, IFN-beta treatment increased mTOR activation, as indicated by S6 phosphorylation in in vitro mixed glial cultures. Taken together, these findings highlight a critical role of type I IFN signaling in seizure progression, potentially via mTOR modulation, and suggest that targeting type I IFNs may offer a promising therapeutic strategy for epilepsy.