Distinct Modulation of High- and Low-Frequency Activity by Midazolam and Neurosteroids in Neocortical Slices

Adverse effects of benzodiazepines are largely mediated by GABA_A receptors containing α1-subunits. Recent efforts to replace benzodiazepines with neurosteroids are promising, but it is unclear to what extent α1-GABA_A receptors are also upregulated by neurosteroids. Here, we investigate how a prototypical benzodiazepine and neurosteroids modify a form of neuronal activity that is controlled by α1-GABA_A receptors. We compared the actions of the benzodiazepine midazolam, the naturally occurring neurosteroid allopregnanolone, and XBD173, a drug that enhances neurosteroidogenesis, on high- (HFA, >50 Hz) and low- (LFA, <50 Hz) frequency action potential activity in cultured neocortical tissue slices derived from wild-type mice via extracellular multi-unit recordings. The effects of midazolam were also quantified in slices from α2/3/5-knock-in-mice, in which the drug acts almost exclusively via α1-GABA_A receptors. In slices derived from α2/3/5-knock-in mice, low nanomolar concentrations of midazolam suppressed HFA in a selective manner. In slices derived from wild-type animals, HFA was also attenuated by midazolam. In contrast, allopregnanolone and XBD173 did not affect HFA but strongly suppressed LFA. Our findings suggest that, in contrast to benzodiazepines, neurosteroids do not dampen HFA, a type of cortical network activity tightly controlled by α1-GABA_A receptors.