Ih and K+ Channels as Mechanistically Novel Targets for Depression Treatment

描述（由申请人提供）：由于不到50%的重度抑郁症（MDD）患者达到完全缓解，因此迫切需要机制上不同的新型抗抑郁药。此外，尽管经过50多年的巨大努力，只有一个或两个机制新药类已开发用于MDD治疗。由于现有技术的限制，研究复杂大脑中选择性类型的神经元的功能以及进一步确定潜在的药物靶点是非常困难的。通过采用病毒介导的基因转移和光遗传学方法，我们定义了大脑奖励回路的腹侧被盖区（VTA）多巴胺（DA）神经元中的神经元可塑性，这对于慢性社会失败（抑郁症模型）的易感性和恢复力是足够和必要的。在这个模型中，一些暴露于慢性社交失败的小鼠表现出抑郁样行为，如社交回避行为或较低的蔗糖摄入量（快感缺乏）（抑郁易感性），而其他小鼠则正常（抑郁恢复力）。在细胞水平上，慢性失败增加了敏感小鼠腹侧被盖区DA神经元的体内放电率和爆发事件，但在弹性亚组中没有。在自由行为的弹性小鼠中，VTA DA神经元中通道视紫红质-2（ChR 2）的光激活（模拟爆发事件）增加了社交互动测试期间的回避行为。为了探索这些神经元中的潜在药物靶点，我们研究了更高病理性放电的离子机制。我发现，Ih（超极化激活阳离子通道）的电流，VTA中的一个重要通道，在突发放电的调节中起着关键作用，在易感小鼠中增加，令人惊讶的是，在弹性亚组中增加得更明显。我还发现，钾（K+）通道功能只在有弹性的小鼠中选择性增加。这些数据强烈支持腹侧被盖区DA神经元的Ih通道是易感表型的基础的被动病理离子机制之一，而K+通道是一种重要的主动离子机制，其驱动较高的放电回到正常水平，并提供有弹性的小鼠成功科普压力条件和避免发展抑郁样行为的能力。因此，我们假设，在这个翻译项目中，无论是被动离子通道阻滞剂或主动离子通道激活剂，抑制腹侧被盖区DA神经元的更高的病理性放电，是抗抑郁药或pro-resilient。与这一假设高度一致，我发现Ih抑制剂具有有趣的快速和持久的抗抑郁作用，这与需要数周才能产生治疗效果的标准抗抑郁药非常不同。更重要的是，我的数据显示，K+通道激活剂倾向于逆转回避行为，其方式与传统抗抑郁药相同。这些一致的研究基于将VTA DA神经元定义为具有病毒介导的基因转移和光遗传学技术的细胞靶点，为MDD治疗提供了非常有前途的新药物靶点，其机制不同于传统的基于单胺的抗抑郁药。

DESCRIPTION (provided by applicant): There is an urgent need for mechanistically distinct new antidepressants as less than 50% of major depressive disorder (MDD) patients achieve full remission. Moreover, despite over 50 years of tremendous efforts, only one or two mechanistically new drug classes have been developed for MDD treatment. Due to a limitation of available techniques, it has been extremely difficult to investigate the function of a selective type of neurons in the complex brain, and to further define potential drug targets. By employing viral-mediated gene transfer and optogenetic approaches, we defined neuronal plasticity, in ventral tegmental area (VTA) dopamine (DA) neurons of the brain reward circuitry, that are both sufficient and necessary to underlie susceptibility and resilience to chronic social defeat, a model of depression. In this model, some mice exposed to chronic social defeat exhibit depression-like behaviors such as social avoidance behavior or lower sucrose intake (anhedonia) (susceptibility to depression), while others are normal (resilience to depression). At the cellular level, chronic defeat increased the in vivo firing rate and bursting events of VTA DA neurons in susceptible mice, but not in the resilient subgroup. In freely-behaving resilient mice, light activation of channelrhodopsin-2 (ChR2) (mimicking bursting events) in VTA DA neurons increased avoidance behavior during social interaction test. To explore potential drug targets in these neurons, we investigated the ionic mechanisms that underlie the higher pathological firing. I found that the current of Ih (hyperpolarization-activated cation channels), an important channel in the VTA that plays a key role in the regulation of burst firing, was increased in susceptible mice, and surprisingly, increased even significantly more in the resilient subgroup. I also found that potassium (K+) channel function was selectively increased only in resilient mice. These data strongly support that Ih channels of VTA DA neurons are one of the passive pathological ion mechanisms that underlie the susceptible phenotype, while K+ channels are an important active ion mechanism that drive the higher firing back to normal levels and provides the ability of resilient mice to successfully cope with stressful conditions and avoid developing depression-like behaviors. We therefore hypothesize, in this translational project, that both passive ion channel blockers or active ion channel activators, that inhibit the higher pathological firing of VTA DA neurons, are antidepressant or pro-resilient. Highly consistent with this hypothesis, I found interesting rapid and long-lasting antidepressant effects of Ih inhibitors, which is very different from standard antidepressants that take weeks to have treatment effects. And more importantly, my data showed that a K+ channel activator tended to reverse avoidance behavior in the same manner as traditional antidepressants. These consistent studies, based on defining VTA DA neurons as cellular targets with viral-mediated gene transfer and optogenetic techniques, provide very promising new drug targets for MDD treatment, which are mechanistically different from traditional monoamine-based antidepressants.