Enduring changes in tonic GABA_A receptor signaling in dentate granule cells after controlled cortical impact brain injury in mice

Changes in functional GABA_AR signaling in hippocampus have previously been evaluated using pre-clinical animal models of either diffuse brain injury or extreme focal brain injury that precludes measurement of cells located ipsilateral to injury. As a result, there is little information about the status of functional GABA_AR signaling in dentate granule cells (DGCs) located ipsilateral to focal brain injury, where significant cellular changes have been documented. We used whole-cell patch-clamp recordings from hippocampal slices to measure changes in GABA_ARs in dentate granule cells (DGCs) at 1-2, 3-5, and 8-13 weeks after controlled cortical impact (CCI) brain injury. Synaptic and tonic GABA_AR currents (I_TonicGABA) were measured in DGCs at baseline conditions and during application of the GABA_AR agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol hydrochloride (THIP) to assess in the function of δ subunit-containing GABA_ARs. DGCs ipsilateral to CCI exhibited no changes in the amplitude of resting I_TonicGABA relative to DGCs after sham-injury or contralateral to CCI. In contrast, there was a significant reduction in the THIP-evoked I_TonicGABA in DGCs ipsilateral to CCI at both time-points. Tonic GABAergic inhibition of DGCs ipsilateral to injury also exhibited reduced responsiveness to the neurosteroid THDOC. I_TonicGABA in DGCs ipsilateral to CCI did not exhibit a change in sensitivity to L655,708, an inverse agonist with selectivity for α₅ subunit-containing GABA_ARs, suggesting a lack of functional change in GABA_ARs containing this subunit. At the 8-13 week time-point, gene expression of GABA_AR subunits expected to contribute to I_TonicGABA (i.e., α₄, α₅ and δ) was not significantly altered by CCI injury in isolated dentate gyrus. Collectively, these results demonstrate enduring functional changes in I_TonicGABA in DGCs ipsilateral to focal brain injury that occur independent of altered gene expression.