Traumatic Brain Injury Broadly Affects GABAergic Signaling in Dentate Gyrus Granule Cells

Traumatic brain injury (TBI) causes cellular and molecular alterations that contribute to neuropsychiatric disease and epilepsy. GABAergic dysfunction figures prominently in the pathophysiology of TBI, yet the effects of TBI on tonic inhibition in hippocampus remain uncertain. We used a mouse model of severe TBI [controlled cortical impact (CCI)] to investigate GABAergic signaling in dentate gyrus granule cells (DGGCs). Basal tonic GABA currents were not affected by CCI. However, tonic currents induced by the δ subunit-selective GABA(A) receptor agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP; 10 μm) were reduced by 44% in DGGCs ipsilateral to CCI (CCI-ipsi), but not in contralateral DGGCs. Reduced THIP currents were apparent one week after injury and persisted up to 15 weeks. The frequency of spontaneous IPSCs (sIPSCs) was reduced in CCI-ipsi cells, but the amplitude and kinetics of sIPSCs were unaffected. Immunohistochemical analysis showed reduced expression of GABA(A) receptor δ subunits and GABA(B) receptor B2 subunits after CCI, by 43% and 40%, respectively. Activation of postsynaptic GABA(B) receptors caused a twofold increase in tonic currents, and this effect was markedly attenuated in CCI-ipsi cells (92% reduction). GABA(B) receptor-activated K(+) currents in DGGCs were also significantly reduced in CCI-ipsi cells, confirming a functional deficit of GABA(B) receptors after CCI. Results indicate broad disruption of GABAergic signaling in DGGCs after CCI, with deficits in both phasic and tonic inhibition and GABA(B) receptor function. These changes are predicted to disrupt operation of hippocampal networks and contribute to sequelae of severe TBI, including epilepsy.