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）患者获得完全缓解，迫切需要机械上不同的新型抗抑郁药。此外，尽管经过50多年的巨大努力，只有一两种机制上的新药被开发出来用于治疗重度抑郁症。由于现有技术的限制，研究复杂大脑中选择性神经元类型的功能以及进一步确定潜在的药物靶点非常困难。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）神经元的神经元可塑性，这是对慢性社会失败（抑郁症的一种模式）的易感性和弹性的充分和必要的基础。在这个模型中，一些暴露于长期社交失败的老鼠表现出类似抑郁的行为，如社交回避行为或低糖摄入量（快感缺乏）（对抑郁的易感性），而另一些则是正常的（对抑郁的抵抗力）。在细胞水平上，慢性失败增加了易感小鼠VTA - DA神经元的体内放电率和破裂事件，但在弹性亚组中没有。在行为自由的弹性小鼠中，VTA DA神经元的通道视紫红质-2 (ChR2)（模拟破裂事件）的光激活增加了社会互动测试中的回避行为。为了探索这些神经元的潜在药物靶点，我们研究了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）是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，Ih（超极化激活阳离子通道）的电流增加了，令人惊讶的是，在弹性亚组中，Ih的电流增加得更明显。我还发现，钾（K+）通道功能仅在弹性小鼠中选择性地增加。这些数据有力地支持了VTA DA神经元的Ih通道是易感表型背后的被动病理离子机制之一，而K+通道是一个重要的主动离子机制，它驱动高放电回到正常水平，并提供弹性小鼠成功应对应激条件和避免发生抑郁样行为的能力。因此，在这个翻译项目中，我们假设，抑制VTA DA神经元较高病理性放电的被动离子通道阻滞剂或活性离子通道激活剂都具有抗抑郁或促恢复作用。与这一假设高度一致的是，我发现了Ih抑制剂有趣的快速和持久的抗抑郁效果，这与标准抗抑郁药需要数周才能产生效果非常不同。更重要的是，我的数据显示，K+通道激活剂倾向于以与传统抗抑郁药相同的方式逆转回避行为。这些一致的研究基于病毒介导的基因转移和光遗传技术将VTA DA神经元定义为细胞靶点，为MDD治疗提供了非常有前途的新药物靶点，这些药物与传统的单胺类抗抑郁药在机制上有所不同。

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.