Age-related trajectories in epileptogenesis and neurological function in an experimental model of post-traumatic epilepsy

Post-traumatic epilepsy (PTE) is a debilitating long-term consequence of traumatic brain injury (TBI), yet the influence of age on epileptogenesis and neurological recovery remains insufficiently understood. Despite the high prevalence of TBI in the elderly, few studies have systematically compared long-term outcomes across age groups. In this study, we investigated age-dependent differences in epileptogenic activity, behavioral and neuropathological outcomes following severe TBI in young and aged male mice. Animals underwent controlled cortical impact and were monitored using 24/7 video-EEG for 120 days to assess epileptogenesis. Longitudinal behavioral assessments evaluated motor, cognitive, and neurological impairments, while histological analyses examined hippocampal neurodegeneration, neuroinflammation, and circuit remodeling. Young TBI mice exhibited delayed epileptogenesis characterized by elevated epileptic biomarkers (fast ripples, interictal spikes and spindles) and greater seizure burden during the chronic phase. In contrast, aged mice showed a significantly lower incidence of PTE and ictal biomarkers but displayed earlier onset. Young mice exhibited persistent motor dysfunction, memory deficits, sustained astrocyte neuroinflammatory responses, and enhanced maladaptive synaptic reorganization within the dentate gyrus than aged cohort. Loss of principal neurons and interneurons, as well as hippocampal neurogenesis, were comparable across age groups, indicating that epileptogenic changes are driven by alterations in network dynamics rather than differences in cell loss or neurogenesis. Collectively, these findings demonstrate that aging reshapes post-traumatic disease trajectories by altering network excitability and cognitive outcomes while selectively dampening seizure activity. This study establishes age as a critical biological variable in PTE research and emphasizes the need for age-specific approaches in experimental design and therapeutic development to mitigate seizure burden and long-term neurological morbidity.