AbstractMost anti-seizure drugs (ASDs) achieve their effects by suppressing neuronal excitability through various drug targets. However, these drug targets are widely expressed in both excitatory and inhibitory neurons. Here, we investigate whether the efficacy of the ASD retigabine (RTG) is altered after removal of the potassium channel subunit KCNQ2, one of its drug targets, from parvalbumin-expressing interneurons (PV-INs). Parvalbumin-Cre (PV-Cre) mice were crossed with Kcnq2-floxed (Kcnq2fl/fl) mice to conditionally delete Kcnq2, the gene encoding KCNQ2, from PV-INs. The efficacy of RTG (10 mg/kg, i.p.) in preventing seizures induced by picrotoxin (PTX, 10 mg/kg, i.p.) and kainic acid (KA, 30mg/kg, i.p.) in conditional knockout mice (cKO, PV-Kcnq2fl/fl) was tested. Immunostaining for KCNQ2 and KCNQ3 and in vitro pharmacological studies with whole-cell recordings were also performed. The cKO mice had no significant change in appearance, body mass, balance, heat sensitivity, depressive behavior, mortality, or EEG spectral power. RTG significantly delayed the onset of PTX- and KA-induced convulsive seizures in cKO mice, but not in wild-type littermates (WT). The expression of both KCNQ2 and KCNQ3 subunits was specifically enriched at the distal axon initial segments (AISs) of hippocampal CA1 PV-INs. In cKO mice, this specific expression and the potassium currents mediated by these subunits were greatly reduced in PV-INs, while their expression in CA1 pyramidal cells (CA1-PCs) remained unchanged. Accordingly, while the ability of RTG to suppress CA1-PC spike activity was unchanged in cKO mice, its suppressive effect on high-frequency spike activity of CA1 PV-INs (elicited by >540pA depolarizing currents) was significantly reduced compared with WT mice. In addition, the RTG-induced suppressive effect on intrinsic membrane excitability of PV-INs in WT mice became absent or decreased in cKO mice. These findings suggest that reducing the suppression of PV-INs by RTG improves its anticonvulsant effect.Key Points(3-5 bullets, no longer than 85 characters each)RTG was effective for seizures only after Kcnq2 was removed from PV-INs.KCNQ2/KCNQ3 was enriched at PV-IN AISs, sites of AP initiation.Kcnq2 removal greatly reduced KCNQ2/KCNQ3 expression and function in CA1 PV-INs.The suppressive effect of RTG on hippocampal PV-INs was blunted in cKO mice.Therefore, the efficacy of RTG may improve with partial sparing of interneurons.
Inferring drought and heat sensitivity across a Mediterranean forest region in southwest Western Australia: a comparison of approaches
