Pharmacological modulation of striatal physiology and repetitive behaviors by M4 PAMs

项目摘要/摘要 重复行为在强迫症(OCD)等障碍中常见， 抽动症(TS)和自闭症谱系障碍(ASD)。这些行为可以产生深远的影响 对患者生活的负面影响，并可能损害他们的学习、进行社会互动和适应的能力 不断变化的环境。而选择性5-羟色胺再摄取抑制剂、抗精神病药物和行为疗法 在治疗这些症状方面是中等有效的，许多患者对这些治疗方法是无效的 迫切需要确定更好的治疗策略来帮助有这些致残症状的患者。这个 纹状体是大脑的一个区域，在整合来自众多大脑结构的信息方面起着关键作用，并且 对调节习惯性和目标导向的行为至关重要。临床和临床前数据的融合表明 过度活跃的多巴胺和谷氨酸能神经传递通过纹状体中的特定回路 可能代表了反常重复行为的共同机制基础。有趣的是，广泛的 我们实验室和其他实验室的研究发现，M_4亚型的乙酰胆碱受体可以 纹状体多巴胺能和谷氨酸能传递的强大调制控制，增加了 M4的选择性激活剂可以逆转可能导致重复行为的病理变化。 在这里，我们提供了初步的数据，证明M4 PAM可以减少SAPAP3 KO中的过度修饰 小鼠(一种表现出重复的过度修饰表型的遗传小鼠模型)。这可能会提供一个 在确定治疗对可用药有抵抗力的致残症状的新方法方面取得突破 治疗。我们假设在显示重复梳理的多个动物模型中的重复行为 与纹状体中过度活跃的谷氨酸和多巴胺释放有关，而M4 PAM治疗 可以通过使这些形式的神经传递正常化来减少重复的行为。我们将检验这一假设 通过一系列电生理和行为学研究，结合使用了转基因 小鼠、光遗传方法和新的药理工具。这些研究将提供重要的 关于M4受体在调节基底节功能和意志中的生理作用的信息 阐明M4 PAM在缓解重复行为方面的治疗潜力。

Project Summary / Abstract Repetitive behaviors are commonly observed in disorders such as Obsessive-Compulsive Disorder (OCD), Tourette’s Syndrome (TS), and Autism Spectrum Disorders (ASDs). These behaviors can have profound negative effects on patients’ lives and can impair their ability to learn, carry out social interactions, and adapt to changing environments. While selective serotonin reuptake inhibitors, antipsychotics, and behavioral therapy are moderately effective in treating these symptoms, many patients are refractory to these therapies and there is a critical need to identify better treatment strategies to help patients with these disabling symptoms. The striatum is a brain region that plays a key role in integrating information from numerous brain structures and is essential to modulating habitual and goal-directed behaviors. Converging clinical and preclinical data suggest that hyperactive dopaminergic and glutamatergic neurotransmission through specific circuits in the striatum may represent common mechanistic underpinnings of abnormal repetitive behaviors. Interestingly, extensive studies from our lab and others have found that the M4 subtype of muscarinic acetylcholine receptor can exert powerful modulatory control over striatal dopaminergic and glutamatergic transmission, raising the possibility that selective activators of M4 could reverse pathological changes that may give rise to repetitive behaviors. Here we provide preliminary data demonstrating that M4 PAMs can reduce excessive grooming in SAPAP3 KO mice (a genetic mouse model that displays a repetitive over-grooming phenotype). This could provide a breakthrough in identifying a novel approach for treatment of disabling symptoms that are resistant to available therapies. We hypothesize that repetitive behaviors in multiple animal models displaying repetitive grooming are associated with hyperactive glutamate and dopamine release in the striatum, and that M4 PAM treatment can reduce repetitive behaviors by normalizing these forms of neurotransmission. We will test this hypothesis through a series of electrophysiological and behavioral studies using a combination of genetically modified mice, optogenetic approaches, and novel pharmacological tools. These studies will provide important information regarding the physiological role of M4 receptors in regulating basal ganglia function and will elucidate the therapeutic potential of M4 PAMs in providing relief from repetitive behaviors.