Developing Neuronal KCNQ Channel Modulators for Mood Disorders

这个为期5年的R61/R33阶段性创新奖，“开发KCNQ通道调节器治疗情绪障碍”， 旨在作为一种新型治疗方法有效地检查神经元KCNQ 2/3钾（K+）通道亚型 抑郁症和相关疾病的目标。抑郁症是最致残的医学疾病之一， 世界各地的情况和目前可用的治疗方法不足以解决这一巨大的公共卫生负担。 大脑奖励系统的功能障碍正在成为抑郁症的一个核心特征， 引起动机、兴趣和对快乐的反应的缺陷（例如，快感缺乏）。拟议 R61/R33项目利用了我们小组的一系列临床前研究，这些研究突出了KCNQ亚型 神经元钾离子通道作为治疗抑郁症的新靶点。模型 系统，KCNQ通道的上调使大脑奖励回路内的病理功能正常化， 逆转快感缺失的表型。在这些数据的基础上，目前的项目将评估奖励电路活动 伴快感缺乏的抑郁症患者接受KCNQ选择性通道开放剂依佐加宾治疗后 [Aim 1]，并将检查奖励回路活动变化与临床相关 症状和行为结果[目标2]。我们的项目利用了概念化和 测量跨物种的奖励处理变化，并利用研究领域标准（RDoC） 正价系统（PVS）作为一个统一的框架。特别是我们的动物和人类工作 这表明在奖励回路中增强KCNQ通道功能可以使行为过程正常化， 映射到PVS的接近动机（奖励期望）和对奖励的初始反应结构。 该项目利用了（1）人类使用的依佐加滨（Potiga，GlaxoSmithKline）的可用性， 独特的一流KCNQ通道开放剂[FDA批准用于治疗癫痫发作]，和（2） 在神经、行为和临床水平上测量奖励处理的可靠方法的可用性 人类的水平。拟议的研究具有推进治疗发现的巨大潜力， 在RDoC框架内的抑郁症。

This 5-year R61/R33 phased-innovation award, “Developing KCNQ Channel Modulators for Mood Disorders,” is designed to efficiently examine the neuronal KCNQ2/3 potassium (K+) channel subtype as a novel treatment target for depression and related conditions. Depressive disorders are among the most disabling medical conditions worldwide and currently available treatments fall short of addressing this large public health burden. Dysfunction within the brain reward system is emerging as a core feature of depressive disorders, in particular giving rise to deficits in motivation, interest, and response to pleasure (e.g., anhedonia). The proposed R61/R33 project capitalizes on a series of preclinical studies from our group that highlight the KCNQ subtype of neuronal potassium (K+) channel as a novel target for the treatment of depressive disorders. In model systems, up-regulation of KCNQ channels normalizes pathological functioning within the brain reward circuit, reversing an anhedonic phenotype. Building on these data, the current project will assess reward circuit activity following treatment with the KCNQ-selective channel opener ezogabine in depressed patients with anhedonia [Aim 1], and will examine the relationship between change in reward circuit activity and clinically relevant symptom and behavior outcomes [Aim 2]. Our project capitalizes on recent advances in conceptualizing and measuring reward-processing alterations across species, and utilizes the Research Domain Criteria (RDoC) domain of Positive Valence Systems (PVS) as a unifying framework. In particular, our animal and human work indicate that enhancing KCNQ channel function within the reward circuit normalizes behavioral processes that map to the PVS constructs of approach motivation (reward expectancy) and initial responsiveness to reward. The project takes advantage of (1) availability of ezogabine (Potiga, GlaxoSmithKline) for human use as a unique first-in-class KCNQ channel opener [FDA-approved for the treatment of seizure disorders], and (2) availability of reliable methods for measuring reward processing at the level of neural, behavioral, and clinical levels in humans. The proposed studies have significant potential to advance treatment discovery for depression within an RDoC framework.