Abstract
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 GABAA receptor agonist THIP (10 µM) were reduced by 44% in DGGCs ipsilateral to CCI (CCI-ipsi), but not in contralateral DGGCs. Reduced THIP currents were apparent 1 week after injury and persisted up to 15 weeks. The frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) was reduced in CCI-ipsi cells, but the amplitude and kinetics of sIPSCs were unaffected. Immunohistochemical analysis showed reduced expression of GABAA receptor δ subunits and GABAB receptor B2 subunits after CCI, by 43% and 40%, respectively. Activation of postsynaptic GABAB receptors caused a 2-fold increase in tonic currents, and this effect was markedly attenuated in CCI-ipsi cells (92% reduction). GABAB receptor-activated K+ currents in DGGCs were also significantly reduced in CCI-ipsi cells, confirming a functional deficit of GABAB receptors after CCI. Results indicate broad disruption of GABAergic signaling in DGGCs after CCI, with deficits in both phasic and tonic inhibition and GABAB receptor function. These changes are predicted to disrupt operation of hippocampal networks and contribute to sequelae of severe TBI, including epilepsy.
Significance statement Traumatic brain injury (TBI) causes cellular and molecular changes that contribute to the clinical sequelae of TBI, including epilepsy, cognitive deficits, and mood disorders. Improved understanding of these cellular and molecular changes will inform therapeutic approaches to potentially disrupt epileptogenesis and treat symptoms. We investigated changes in GABAergic signaling of dentate gyrus granule cells (DGGCs) in a preclinical model of severe TBI (controlled cortical impact) and identified early and persistent deficits in expression and function of both synaptic and extrasynaptic GABAA receptors and GABAB receptors. These broad changes in GABAergic signaling will alter function of DGGCs and are predicted to perturb hippocampal networks and contribute to epileptogenesis and cognitive deficits after TBI.
Footnotes
The authors declare no competing financial interests.
Merit Award I01 BX002745-01A1
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
