Molecular and functional changes in GABAergic transmission during epileptogenesis in a rat model of post-traumatic epilepsy

Traumatic brain injury (TBI) is one of the leading causes of structural epilepsy. Our objective was to investigate the molecular and functional dysregulation of GABAergic neurotransmission during a wide time window from acute to chronic phases of epileptogenesis after TBI. Perilesional and thalamic tissues sampled from a clinically relevant animal model of post-traumatic epilepsy induced by lateral fluid-percussion injury were investigated using in situ hybridization, immunohistochemistry and RNA sequencing. For functional analysis, we utilized a membrane microtransplantation technique in Xenopus oocytes in order to overcome the technical difficulties that would stem from recording directly from highly damaged lesional and perilesional brain tissues. Already at 6 to 24 h post-TBI we found a dysregulation in the expression of GABAAR beta 3- and delta-subunits, which persisted for up to 4 months. Further, gene set enrichment analysis revealed a negative enrichment of GABA receptor signaling in the perilesional cortex and ipsilateral thalamus. These changes occurred in parallel to the dysregulation of the two main cation-chloride cotransporter genes (Slc12a2 and Slc12a5) both in the perilesional cortex and the ipsilateral thalamus. Our functional analysis revealed that the GABA current reversal potential (EGABA) was shifted towards more depolarized values in the perilesional cortex and ipsilateral thalamus. Our data demonstrate a rapid onset and long-lasting duration of GABAergic dysfunction after TBI and support the hypothesis that an early treatment with agents modulating the GABAergic transmission in the thalamo-cortical-thalamic circuitry may suppress early seizures as well as prevent or slow down epileptogenesis after TBI.