Abstracts

Rationale: Despite the association between traumatic brain injury (TBI) and acquired temporal lobe epilepsy (TLE), mechanisms underlying posttraumatic epileptogenesis are not known. TBI results in cell loss and aberrant cellular connectivity and signaling that is associated with hyperexcitability in cortical structures. In hippocampal dentate granule cells (DGCs), tonic GABA currents (I_Tonic) are important for both information processing and regulation of excitability in hippocampal circuits, but effects of TBI on I_Tonic are incompletely understood. This study used a murine model of posttraumatic epilepsy to evaluate TBI-induced changes to I_Tonic in DGCs. Methods: Severe unilateral controlled cortical impact (CCI; impact depth= 1.0 mm) was administered to 6-8 week old male mice. Early (1-2 wks) and late (8-13 wks) post-injury time points were analyzed. Coronal slices were taken from both hemispheres (ipsilateral and contralateral to CCI). Whole-cell patch clamp recordings were performed on DGCs in the presence of kynurenic acid (1mM). Baseline I_Tonic was measured after application of bicuculline (30 µM), zolpidem (1 µM), or gaboxadol (THIP; 3 µM). Responses to zolpidem or THIP were assessed based on the relative selectivity of these drugs for GABA_A receptor alpha-1 and delta subunits, respectively. I_Tonic values were normalized to cell capacitance. Results: Baseline I_Tonic amplitude was not significantly altered by CCI injury. THIP application resulted in an outward shift in holding current (THIP-sensitive I_Tonic). At 1-2 wks post-CCI, DGCs ipsilateral to the injury exhibited a significantly smaller THIP-sensitive I_Tonic (1.84+/- 0.32 pA/pF) relative to cells from sham animals (3.06+/- 0.35 pA/pF; p < 0.05) and tended to be reduced relative to cells contralateral to the injury (3.11+/- 0.50 pA/pF). At 8-13 wks post-CCI, ipsilateral DGCs exhibited a significantly reduced THIP-sensitive I