Sex differences in post-traumatic epileptogenesis and neurological dysfunction following traumatic brain injury

Post-traumatic epilepsy (PTE) is a disabling long-term consequence of traumatic brain injury (TBI), but the role of biological sex on epileptogenesis and recovery remains unclear. Here, we comprehensively characterized chronic PTE development and neurological outcomes in adult male and female mice after severe TBI by controlled cortical impact. Animals underwent continuous video-EEG monitoring for 120 days, serial behavioral, motor, and cognitive testing, and terminal histological assessment of neurodegeneration, neuroinflammation, neurogenesis, and circuit remodeling. Females had a lower incidence of PTE, lower cohort-level seizure burden, a higher seizure threshold, and fewer epileptiform discharges than males. The burden of epileptogenic biomarkers of ripples, fast-ripples, interictal-spikes, and sleep-spindles were also reduced or delayed in females than males. However, among female animals that developed PTE, seizure latency and ictal burden were comparable between sexes, indicating that female sex primarily reduced susceptibility to epilepsy rather than the severity of chronic epilepsy. Females experienced less post-injury health deterioration, recovered neurological and motor function more rapidly, and performed better in recognition-memory and spatial-learning tasks, although chronic cognitive deficits persisted. At 120 days, females showed greater hippocampus neuronal preservation and markedly attenuated astrogliosis and microgliosis than males. Nevertheless, both sexes nevertheless exhibited hippocampal principal neuron and parvalbumin(+) interneuron loss, reduced dentate gyrus neurogenesis, and mossy fiber remodeling. Collectively, these findings identify biological sex as a major determinant of post-traumatic disease trajectory, separating susceptibility to PTE from the severity of epilepsy once established. Sex-stratified outcomes may therefore improve biomarker development and guide sex-specific preventive therapies for PTE. This study reveals a female-resilient phenotype that limits epileptogenesis while leaving chronic network, cognitive deficits, and structural abnormalities unresolved after injury.