Department of Psychiatry, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Aptuit, Verona, Italy.
Neuropsychopharmacology. 2018 Jan;43(2):435-444. doi: 10.1038/npp.2017.155. Epub 2017 Aug 31.
Kv3.1 and Kv3.2 voltage-gated potassium channels are expressed on parvalbumin-positive GABAergic interneurons in corticolimbic brain regions and contribute to high-frequency neural firing. The channels are also expressed on GABAergic neurons of the basal ganglia, substantia nigra, and ventral tegmental area (VTA) where they regulate firing patterns critical for movement control, reward, and motivation. Modulation of Kv3.1 and Kv3.2 channels may therefore have potential in the treatment of disorders in which these systems have been implicated, such as bipolar disorder. Following the recent development of a potassium channel modulator, AUT1-an imidazolidinedione compound that specifically increases currents mediated by Kv3.1 and Kv3.2 channels in recombinant systems-we report that the compound is able to reverse 'manic-like' behavior in two mouse models: amphetamine-induced hyperactivity and ClockΔ19 mutants. AUT1 completely prevented amphetamine-induced hyperactivity in a dose-dependent manner, similar to the atypical antipsychotic, clozapine. Similar efficacy was observed in Kv3.2 knockout mice. In contrast, AUT1 was unable to prevent amphetamine-induced hyperactivity in mice lacking Kv3.1 channels. Notably, Kv3.1-null mice displayed baseline hyperlocomotion, reduced anxiety-like behavior, and antidepressant-like behavior. In ClockΔ19 mice, AUT1 reversed hyperactivity. Furthermore, AUT1 application modulated firing frequency and action potential properties of ClockΔ19 VTA dopamine neurons potentially through network effects. Kv3.1 protein levels in the VTA of ClockΔ19 and WT mice were unaltered by acute AUT1 treatment. Taken together, these results suggest that the modulation of Kv3.1 channels may provide a novel approach to the treatment of bipolar mania.
Kv3.1 和 Kv3.2 电压门控钾通道表达于皮质边缘脑区的 GABA 能中间神经元上，参与高频神经放电。这些通道也表达于基底神经节、黑质和腹侧被盖区（VTA）的 GABA 能神经元上，调节对运动控制、奖励和动机至关重要的放电模式。因此，Kv3.1 和 Kv3.2 通道的调制可能对涉及这些系统的疾病的治疗具有潜在作用，例如双相情感障碍。在最近开发了一种钾通道调节剂 AUT1（一种咪唑烷二酮化合物，特异性增加重组系统中介导 Kv3.1 和 Kv3.2 通道的电流）之后，我们报告该化合物能够逆转两种小鼠模型中的“躁狂样”行为：安非他命诱导的过度活动和 ClockΔ19 突变体。AUT1 以剂量依赖性方式完全阻止安非他命诱导的过度活动，类似于非典型抗精神病药氯氮平。在 Kv3.2 敲除小鼠中观察到类似的疗效。相比之下，AUT1 无法阻止缺乏 Kv3.1 通道的小鼠中的安非他命诱导的过度活动。值得注意的是，Kv3.1 敲除小鼠表现出基础过度活跃、焦虑样行为减少和抗抑郁样行为。在 ClockΔ19 小鼠中，AUT1 逆转了过度活动。此外，AUT1 的应用调节了 ClockΔ19 和 WT 小鼠 VTA 多巴胺神经元的放电频率和动作电位特性，可能通过网络效应。急性 AUT1 处理未改变 ClockΔ19 和 WT 小鼠 VTA 中的 Kv3.1 蛋白水平。综上所述，这些结果表明，Kv3.1 通道的调制可能为双相情感躁狂症的治疗提供一种新方法。
