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

Ih 和 K 通道作为抑郁症治疗的机制新靶点

• 批准号: 8534855
• 负责人: Allyson Kimberly Friedman
• 金额: $ 5.66万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2014-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8534855
• 关键词: Adverse effects; Anhedonia; Animals; Antidepressive Agents; Back; Basic Science; Behavior; Behavioral; Brain; Chronic; Complex; Data; Depressed mood; Development; Disease remission; Dopamine; Drug Targeting; Event; Exhibits; Exposure to; Frequencies; Gene Transfer; Genes; Goals; Hyperactive behavior; In Vitro; Intake; Ion Channel; Ions; Light; Link; Maintenance; Major Depressive Disorder; Mediating; Mental Depression; Mental disorders; Mission; Modeling; Molecular; Mus; Neuronal Plasticity; Neurons; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Play; Population; Potassium; Potassium Channel; Predisposition; Process; Property; Psyche structure; Psychophysiology; Regulation; Research; Series; Social Interaction; Solid; Stress; Subgroup; Sucrose; Techniques; Testing; Therapeutic; Translational Research; Ventral Tegmental Area; Viral; Work; avoidance behavior; base; cellular targeting; clinically relevant; coping; coping mechanism; dopaminergic neuron; hyperpolarization-activated cation channel; in vivo; inhibitor/antagonist; innovation; interest; ion channel blocker; mental state; monoamine; neurophysiology; neurotensin mimic 2; novel; optogenetics; pre-clinical; psychologic; resilience; reward circuitry; social; treatment effect

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.

描述(由申请人提供)：由于只有不到50%的重度抑郁障碍(MDD)患者完全缓解，迫切需要机械上独特的新抗抑郁药物。此外，尽管经过了50多年的巨大努力，但只有一两种机械性的新药物类别被开发出来用于MDD的治疗。由于现有技术的限制，很难研究复杂大脑中特定类型神经元的功能，并进一步确定潜在的药物靶点。通过病毒介导的基因转移和光遗传学方法，我们定义了大脑回报回路腹侧被盖区(VTA)多巴胺(DA)神经元的可塑性，这是构成抑郁症模型-慢性社会失败的易感性和弹性的充分和必要的基础。在这个模型中，一些暴露在慢性社交失败中的小鼠表现出类似抑郁的行为，如社交回避行为或较低的蔗糖摄入量(缺乏快感)(易患抑郁症)，而其他小鼠则正常(易患抑郁症)。在细胞水平上，慢性挫败增加了易感小鼠体内VTA DA神经元的放电率和爆裂事件，但在弹性亚群中没有增加。在行为自由的弹性小鼠中，VTA DA神经元中通道视紫红质-2(ChR2)(模拟爆发事件)的光激活增加了社交互动测试中的回避行为。为了探索这些神经元中潜在的药物靶点，我们研究了高病理放电背后的离子机制。我发现，在易感的小鼠中，超极化激活的阳离子通道(Ih)的电流增加，令人惊讶的是，在弹性亚组中增加得更多。我还发现，只有在有弹性的小鼠身上，钾(K+)通道的功能才会选择性地增强。这些数据有力地支持了VTA DA神经元的Ih通道是导致易感表型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，可以驱动较高的放电恢复到正常水平，并为有弹性的小鼠提供成功应对应激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还是主动离子通道激活剂，抑制VTA DA神经元更高的病理性放电，都是抗抑郁或前弹性的。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作用，这与标准的抗抑郁药非常不同，后者需要数周才能产生治疗效果。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将VTA DA神经元定义为病毒介导的基因转移和光遗传技术的细胞靶点，为MDD的治疗提供了非常有前途的新药物靶点，这些药物在机制上不同于传统的单胺类抗抑郁药物。