Zolpidem Profoundly Augments Spared Tonic GABAAR Signaling in Dentate Granule Cells Ipsilateral to Controlled Cortical Impact Brain Injury in Mice

Type A GABA receptors (GABA(A)Rs) are pentameric combinations of protein subunits that give rise to tonic (I-TonicGABA) and phasic (i.e., synaptic; I-SynapticGABA) forms of inhibitory GABA(A)R signaling in the central nervous system. Remodeling and regulation of GABA(A)R 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(A)R 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(A)Rs, was used to test for changes in GABA(A)R signaling of DGCs due to its selectivity for alpha(1) subunit-containing GABA(A)Rs. Electric charge transfer and statistical percent change were analyzed in order to directly compare tonic and phasic GABA(A)R signaling and to account for zolpidem's ability to modify multiple parameters of GABA(A)R 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(A)R charge transfer mediated by tonic vs. synaptic currents at both time-points tested, whereas gene expression of GABA(A)R alpha(1), alpha(2), alpha(3), and gamma(2) 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.

Automated summary

This study provides a detailed analysis of GABA(A)R signaling in mouse dentate granule cells (DGCs) after brain injury. The researchers observed that DGCs on the same side as the injury were more responsive to GABA(A)R signaling and that the drug Zolpidem can modify this signaling. Additionally, there were no changes in gene expression of GABA(A)R subunits after brain injury.