GABAA receptor subunit modulation reversed electrophysiological network alterations after blast exposure in rat organotypic hippocampal slice cultures

Abstract

Throughout training and deployment, some military service members are frequently exposed to shock waves due to blasts, and some complain of myriad neurological symptoms. In rat organotypic hippocampal slice cultures (OHSCs), blast-induced traumatic brain injury (bTBI) causes deficits in some electrophysiological measures, like long term potentiation, a neuronal correlate for learning and memory. In this study, we further characterized the alterations in the hippocampal network of OHSCs following a single moderate blast exposure. Connectivity and clustering coefficients were reduced across the hippocampal network following bTBI, despite the lack of changes in the firing rate, spike amplitude, spike duration, or inter-spike interval. However, interrogation with the GABA_A receptor antagonist, bicuculline, revealed additional significant differences between injured and control slices in measures of spike amplitude, spike duration, connectivity, and clustering. bTBI also significantly reduced expression of the α1 and α5 GABA_A receptor subunits. Treatment with the FDA-approved histone deacetylase inhibitor suberanilohydroxamic acid (SAHA) restored the α1 subunit and attenuated deficits in network measures, like connectivity and clustering coefficients. These findings suggest that GABA_A receptors may be implicated in neuronal network changes in OHSCs following bTBI, and their recovery may be a viable therapeutic intervention to mitigate injury-induced neurological symptoms.

Keywords: Blast traumatic brain injury; Electrophysiology; GABA(A) receptor; Hippocampus; Neuronal network.