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

Abstract

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 GABA_AR β3- and δ-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 (E_GABA) 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.

Keywords: Cation-chloride cotransporter gene; Electrophysiology; Epileptogenesis; GABAergic signaling; Traumatic brain injury.