Neurophysiological and neuroinflammatory adaptations to seizure activity in aging

The pathophysiological impact of late-onset seizures on the brain is not well understood. Here, we investigated whether an initial pattern of generalized seizures (GS) with an electrographically defined ictal-interictal continuum, occurring at middle age (12-13 months old) in a mouse model, induces long-term neurophysiological and cellular changes, compared to young-adults (2-3 months old). In young-adults, the initial patterns of GS were associated with sporadic spike and wave discharges (SWDs) in the long term. In contrast, in late middle-age mice, GS were sufficient to promote spontaneous case-specific seizures over time, together with SWDs. This group presented increased spike activity and alterations in delta-theta wave patterns during both wakefulness and sleep, compared to age-matched sham controls. These long-term electrophysiological changes were accompanied by modifications in open field behavior, but not by histological evidence of hippocampal sclerosis or cortical atrophy. Because seizures can induce neuroinflammation, we investigated biomarkers of glial reactivity. The late middle-age group exhibited more pronounced increases over time in hippocampal and cortical GFAP⁺ density and IBA1⁺ cell number following GS. Finally, we investigate the long-term transcriptomic footprints that may develop in response to seizures and age. RNA sequencing, adjusted for multiple comparisons, revealed elevated immune-related transcripts (Defb1, Pglyrp1, Bdkrb2) and cell cycle/growth regulators (Cdkn1a, PAX7) in late middle-age mice two months after GS compared to young-adults. The initial GS pattern in middle-age elicits a maladaptive response in the long-term, unlike in young-adults, characterized by spontaneous and abnormal electrographic activity. This outcome was accompanied by inflammaging-related cellular and transcriptomic markers, indicating heightened vulnerability of the aging brain to seizures.