Allopregnanolone effects on inhibition in hippocampal parvalbumin interneurons.

Allopregnanolone (AlloP) is a neurosteroid that potentiates ionotropic GABAergic (GABA A ) inhibition and is approved 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 δ subunit. Despite previous evidence for selective effects of AlloP on α4/δ-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 δ subunits with α1 subunits. Here we hypothesized that native α1/δ receptors in hippocampal fast-spiking interneurons may provide a preferred substrate for AlloP. Contrary to the hypothesis, electrophysiology from genetically 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 µM GABA did augment tonic current, which was not primarily through δ-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 interneurons possess low sensitivity to AlloP and suggest they are unlikely contributors to mood-altering effects of neurosteroids through GABA effects. Significance statement AlloP is an endogenous positive allosteric modulator of GABA A receptors and appears to have antidepressant effects triggered faster than traditional medications. The antidepressant mechanism of AlloP is largely unknown and we tested whether inhibition of parvalbumin interneurons in mouse hippocampus could participate. Our results indicate that PV interneurons possess low sensitivity to AlloP despite favorable receptor subunit composition.