期刊
EXPERIMENTAL NEUROLOGY
卷 277, 期 -, 页码 178-189出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.expneurol.2016.01.005
关键词
GABA(A) receptors; Tonic GABA current; Controlled cortical impact; Traumatic brain injury; Post-traumatic epilepsy
资金
- Department of Defense (USAMRMC) Grant [W81XWH-11-1-0502]
- American Epilepsy Society
- Lennox and Lombroso Trust for Epilepsy Research and Training
Changes in functional GABA(A)R 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(A)R 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(A)Rs 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(A)R currents (I-TronicGABA) were measured in DGCs at baseline conditions and during application of the GABA(A)R agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol hydrochloride (THIP) to assess in the function of 8 subunit-containing GABA(A)Rs. 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-TronicGABA 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 alpha(5) subunit-containing GABA(A)Rs, suggesting a lack of functional change in GABA(A)Rs containing this subunit. At the 8-13 week time-point, gene expression of GABA(A)R subunits expected to contribute to I-TronicGABA (i.e., alpha(4), alpha(5) and delta) 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. (C) 2016 Elsevier Inc All rights reserved.
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