Developing Neuronal KCNQ Channel Modulators for Mood Disorders

这项为期5年的R61/R33阶段性创新奖是“为情绪障碍开发KCNQ通道调制器”， 旨在有效地检测神经元KCNQ2/3钾(K)通道亚型作为一种新的治疗方法 抑郁症及相关疾病的目标。抑郁症是最令人丧失能力的医学疾病之一。 世界范围内的条件和目前可用的治疗方法不能解决这一巨大的公共卫生负担。 尤其是，大脑奖赏系统内的功能障碍正在成为抑郁症的核心特征 导致缺乏动力、兴趣和对快乐的反应(例如，快感缺失)。建议数 R61/R33项目利用了我们小组的一系列临床前研究，突出了KCNQ亚型 神经元钾(K)通道作为治疗抑郁障碍的新靶点。在模型中 系统中，KCNQ通道的上调使大脑奖励回路内的病理功能正常化， 逆转一种非享乐性的表型。在这些数据的基础上，目前的项目将评估奖励回路活动 KCNQ选择性通道开放剂ezogabine治疗抑郁症快感缺乏症 [目标1]，并将研究奖赏回路活动的变化与临床相关性之间的关系 症状和行为结果[目标2]。我们的项目利用了最近在概念化和 测量不同物种的奖励处理变化，并使用研究领域标准(RDoC) 作为统一框架的正价系统(PVS)域。特别是，我们的动物和人类的工作 表明增强奖励回路内的KCNQ通道功能使行为过程正常化 映射到接近动机(奖励期望)和对奖励的初始反应的PVS结构。 该项目利用(1)ezogabine(Potiga，GlaxoSmithKline)可供人类用作 独一无二的一流KCNQ通道开放器[FDA批准用于治疗癫痫障碍]，以及(2) 在神经、行为和临床水平上衡量奖励处理的可靠方法的可用性 在人类中的水平。拟议中的研究具有极大的潜力来推进治疗发现 RDoC框架内的抑郁。

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.