Microglia-Dependent Changes of Extrasynaptic GABA-A Receptor Expression and Function in Thalamocortical Neurons After Traumatic Brain Injury (TBI)
Abstract number :
3.003
Submission category :
1. Basic Mechanisms / 1A. Epileptogenesis of acquired epilepsies
Year :
2023
Submission ID :
841
Source :
www.aesnet.org
Presentation date :
12/4/2023 12:00:00 AM
Published date :
Authors :
Presenting Author: Amber Nolan, MD PhD – University of Washington
Ryan O'Boyle, B.S. – Laboratory Medicine and Pathology – University of Washington; Alicia Feichtinbiner, BS – Laboratory Medicine and Pathology – University of Washington; Christopher Ransom, MD PhD – Epilepsy Center of Excellence, Neurology – VA Puget Sound, University of Washington
Rationale: Traumatic brain injury (TBI) induces cellular and molecular changes that contribute to neuropsychiatric sequelae of TBI, including epilepsy. TBI-induced alterations of GABAergic signaling and GABA receptor expression/function are known to occur in cortical and hippocampal neurons, but little is known about how TBI affects GABAergic signaling in thalamocortical neurons.
Methods: We used a mouse model of severe TBI (controlled cortical impact, CCI), patch clamp techniques, and immunohistochemistry to investigate changes in δ subunit-containing, extrasynaptic GABAA receptor function in thalamocortical neurons (mediodorsal nucleus).
Results: Tonic GABA currents due to endogenous ambient GABA and in the presence of the GABAA receptor δ-subunit selective agonist THIP were significantly reduced two to four weeks after TBI compared to sham-treated animals. Tonic GABA currents were also reduced at chronic timepoints after TBI (i.e., two to four months). Our CCI model does not cause direct structural injury to thalamus, but there were prominent changes in the number and morphology of IBA1+ microglia after TBI. We hypothesized that microglia-dependent neuroinflammation plays a critical role in the observed changes in tonic GABA currents. To test this, we treated animals with the CSF1 receptor antagonist PLX5622 (PLX) for two weeks to deplete microglia prior to CCI and continued this treatment until electrophysiological assessment. This treatment effectively depleted IBA1+ microglia and occluded TBI effects on tonic GABA currents; in PLX-treated mice there were no significant difference in tonic GABA currents between sham and TBI groups.
Conclusions: These results show for the first time that TBI alters expression and function of δ subunit-containing GABAA receptors in thalamocortical neurons and that TBI-induced changes in GABAA receptor d subunits are strongly dependent on microglia. Dysfunction of GABAA receptors in thalamocortical neurons may contribute to neuropsychiatric symptoms and epileptogenesis after TBI.
Funding: Work supported by Dept of Veterans Affairs,BLR&D Merit Review 2 I01 BX002745-06A2 (CR)
Basic Mechanisms