Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, United States of America; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, 1250 Moursund Street, Houston, TX 77030, United States of America.
Department of Neurology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, United States of America.
Exp Neurol. 2022 Sep;355:114141. doi: 10.1016/j.expneurol.2022.114141. Epub 2022 Jun 9.
Anti-seizure 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 parvalbumin-expressing interneurons (PV-INs). Parvalbumin-Cre (PV-Cre) mice were crossed with Kcnq2-floxed (Kcnq2) mice to conditionally delete Kcnq2 from PV-INs. In these conditional knockout mice (cKO, PV-Kcnq2), RTG (10 mg/kg, i.p.) significantly delayed the onset of either picrotoxin (PTX, 10 mg/kg, i.p)- or kainic acid (KA, 30 mg/kg, i.p.)-induced convulsive seizures compared to vehicle, while RTG was not effective in wild-type littermates (WT). Immunostaining for KCNQ2 and KCNQ3 revealed that both subunits were enriched at axon initial segments (AISs) of hippocampal CA1 PV-INs, and their specific expression was selectively abolished in cKO mice. Accordingly, the M-currents recorded from CA1 PV-INs 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 PV-INs was significantly reduced compared with WT mice. In addition, the RTG-induced suppression on intrinsic membrane excitability of PV-INs in WT mice was significantly reduced in cKO mice. These findings suggest that preventing RTG from suppressing PV-INs improves its anticonvulsant effect.
抗癫痫药物（ASD）的靶点广泛存在于兴奋性和抑制性神经元中。目前尚不清楚 ASD 对抑制性神经元的作用是否会抵消其对兴奋性神经元的有益作用（反之亦然），从而降低 ASD 的疗效。在这里，我们研究了在从表达 Parvalbumin 的中间神经元（PV-INs）中去除 Kv7 钾通道亚基 KCNQ2（其药物靶点之一）后，ASD 瑞替加滨（RTG）的疗效是否会改变。Parvalbumin-Cre（PV-Cre）小鼠与 Kcnq2 基因敲除（Kcnq2）小鼠杂交，以条件性敲除 PV-INs 中的 Kcnq2。在这些条件性敲除小鼠（cKO，PV-Kcnq2）中，与载体相比，RTG（10mg/kg，腹腔注射）显著延迟了胡椒碱（PTX，10mg/kg，腹腔注射）或海人酸（KA，30mg/kg，腹腔注射）诱导的惊厥发作的发作，而 RTG 在野生型同窝仔鼠（WT）中无效。KCNQ2 和 KCNQ3 的免疫染色显示，这两个亚基在海马 CA1 PV-INs 的轴突起始段（AIS）丰富，并且在 cKO 小鼠中它们的特异性表达被选择性消除。相应地，从 CA1 PV-INs 记录的 M 电流及其对 RTG 的敏感性在 cKO 小鼠中显著降低。虽然 RTG 抑制海马切片中 CA1 兴奋性神经元的能力在 cKO 小鼠中没有改变，但与 WT 小鼠相比，其对 CA1 PV-INs 尖峰活动的抑制作用明显降低。此外，与 WT 小鼠相比，RTG 诱导的 WT 小鼠 PV-INs 内在膜兴奋性的抑制作用在 cKO 小鼠中明显降低。这些发现表明，防止 RTG 抑制 PV-INs 可提高其抗惊厥作用。
