Zolpidem Profoundly Augments Spared Tonic GABA_AR Signaling in Dentate Granule Cells Ipsilateral to Controlled...

Type A GABA receptors (GABA_ARs) are pentameric combinations of protein subunits that give rise to tonic (I_TonicGABA) and phasic (i.e., synaptic; I_SynapticGABA) forms of inhibitory GABA_AR signaling in the central nervous system. Remodeling and regulation of GABA_AR protein subunits are implicated in a wide variety of healthy and injury-dependent states, including epilepsy. The present study undertook a detailed analysis of GABA_AR signaling using whole-cell patch clamp recordings from mouse dentate granule cells (DGCs) in coronal slices containing dorsal hippocampus at 1-2 or 8-13 weeks after a focal, controlled cortical impact (CCI) or sham brain injury. Zolpidem, a benzodiazepine-like positive modulator of GABA_ARs, was used to test for changes in GABA_AR signaling of DGCs due to its selectivity for α₁ subunit-containing GABA_ARs. Electric charge transfer and statistical percent change were analyzed in order to directly compare tonic and phasic GABA_AR signaling and to account for zolpidem's ability to modify multiple parameters of GABA_AR kinetics. We observed that baseline I_TonicGABA is preserved at both time-points tested in DGCs ipsilateral to injury (Ipsi-DGCs) compared to DGCs contralateral to injury (Contra-DGCs) or after sham injury (Sham-DGCs). Interestingly, application of zolpidem resulted in modulation of I_TonicGABA across groups, with Ipsi-DGCs exhibiting the greatest responsiveness to zolpidem. We also report that the combination of CCI and acute application of zolpidem profoundly augments the proportion of GABA_AR charge transfer mediated by tonic vs. synaptic currents at both time-points tested, whereas gene expression of GABA_AR α₁, α₂, α₃, and γ₂ subunits is unchanged at 8-13 weeks post-injury. Overall, this work highlights the shift toward elevated influence of tonic inhibition in Ipsi-DGCs, the impact of zolpidem on all components of inhibitory control of DGCs, and the sustained nature of these changes in inhibitory tone after CCI injury.