TITLE: Removal of KCNQ2 from Parvalbuminexpressing Interneurons Improves AntiSeizure Efficacy of Retigabine Abbreviated Title: InterneuronSparing Improves Seizure Drug Efficacy
semanticscholar(2021)
摘要
250 words maximum): Antiseizure drug (ASD) targets are widely expressed in both excitatory and inhibitory neurons. It remains unknown if the action of an ASD upon inhibitory neurons could counteract its beneficial effects on excitatory neurons (or vice versa), thereby reducing the efficacy of the ASD. Here, we examine whether the efficacy of the ASD retigabine (RTG) is altered after removal of the Kv7 potassium channel subunit KCNQ2, one of its drug targets, from parvalbuminexpressing interneurons (PVINs). ParvalbuminCre (PVCre) mice were crossed with Kcnq2floxed (Kcnq2fl/fl) mice to conditionally delete Kcnq2 from PVINs. In these conditional knockout mice (cKO, PVKcnq2fl/fl), RTG (10 mg/kg, i.p.) significantly delayed the onset of either picrotoxin (PTX, 10 mg/kg, i.p) or kainic acid (KA, 30mg/kg, i.p.)induced convulsive seizures compared to vehicle, while RTG was not effective in wildtype littermates (WT). Immunostaining for KCNQ2 and KCNQ3 revealed that both subunits were enriched at axon initial segments (AISs) of hippocampal CA1 PVINs, and their specific expression was selectively abolished in cKO mice. Accordingly, the Mcurrents recorded from CA1 PVINs and their sensitivity to RTG were significantly reduced in cKO mice. While the ability of RTG to suppress CA1 excitatory neurons in hippocampal slices was unchanged in cKO mice, its suppressive effect on the spike activity of CA1 PVINs was significantly reduced compared with WT mice. In addition, the RTGinduced suppression on intrinsic membrane excitability of PVINs in WT mice was significantly reduced in cKO mice. These findings suggest that preventing RTG from suppressing PVINs improves its anticonvulsant effect.
更多查看译文
AI 理解论文
溯源树
样例
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要