Hippocampal circuit remodeling in post-traumatic epileptogenesis: inhibitory dysfunction, glial homeostatic failure, and therapeutic opportunities

Traumatic brain injury (TBI) is a major cause of acquired epilepsy, yet no established therapy prevents the transition from brain injury to post-traumatic epilepsy (PTE). Although the primary lesion frequently involves neocortex, the hippocampus undergoes rapid and persistent cellular and circuit remodeling and is a major candidate substrate for epileptogenesis. This review evaluates hippocampal PTE through a dentate-gate framework in which three interacting dimensions determine network stability: inhibitory control, structural circuit topology, and extracellular/glial homeostasis. TBI can selectively disrupt hippocampal interneuron populations and GABAergic signaling, generate recurrent excitatory connectivity and mossy-fiber sprouting, alter the production and integration of adult-born granule cells, and induce persistent astrocytic, inflammatory, and blood–brain barrier responses. Not all of these observations carry the same weight as evidence for epileptogenesis. We distinguish injury-associated changes from abnormalities enriched in animals that later develop spontaneous PTE and from mechanisms whose targeted manipulation alters spontaneous seizure development. Direct intervention evidence includes suppression of dentate granule-cell mechanistic target of rapamycin (mTOR) signaling and reconstruction of hippocampal inhibitory circuitry with medial ganglionic eminence-derived interneuron precursors, whereas genetic loss of astrocytic aquaporin-4 worsens post-traumatic spontaneous seizures, supporting a causal contribution of extracellular homeostasis. By contrast, several compelling pathways - including altered glutamate transport, connexin signaling, and astrocytic TGF-β responses to blood–brain barrier dysfunction - still require direct testing against spontaneous PTE endpoints. Hippocampal electrophysiological and imaging abnormalities also offer candidate biomarkers for stratifying risk during the latent period. We propose that PTE emerges not from a single lesion but from time-dependent failure of coordinated dentate homeostasis, with different mechanisms dominating at different stages after injury. Organizing the literature in this way highlights testable mechanistic gaps and opportunities for biomarker-guided disease-modifying therapy.