Allopregnanolone Effects on Inhibition in Hippocampal Parvalbumin Interneurons

Allopregnanolone (AlloP) is a neurosteroid that potentiates ionotropic GABAergic (GABA_A) inhibition and is ap-proved for treating postpartum depression in women. Although the antidepressant mechanism of AlloP is largely unknown, it could involve selective action at GABA_A receptors containing the d subunit. Despite previ-ous evidence for selective effects of AlloP on a4/d-containing receptors of hippocampal dentate granule cells (DGCs), other recent results failed to demonstrate selectivity at these receptors (Lu et al., 2020). In contrast to DGCs, hippocampal fast-spiking parvalbumin (PV) interneurons express an unusual variant partnership of d subunits with a1 subunits. Here, we hypothesized that native a1/d receptors in hippocampal fast-spiking inter-neurons may provide a preferred substrate for AlloP. Contrary to the hypothesis, electrophysiology from genet-ically tagged PV interneurons in hippocampal slices from male mice showed that 100 nM AlloP promoted phasic inhibition by increasing the sIPSC decay, but tonic inhibition was not detectably altered. Co-application of AlloP with 5 mM GABA did augment tonic current, which was not primarily through d-containing receptors. Furthermore, AlloP decreased the membrane resistance and the number of action potentials of DGCs, but the impact on PV interneurons was weaker than on DGCs. Thus, our results indicate that hippocampal PV inter-neurons possess low sensitivity to AlloP and suggest they are unlikely contributors to mood-altering effects of neurosteroids through GABA effects.