Cortical GABAergic mechanisms underlying rapid and sustained antidepressant responses

这个项目描述了罗切斯特大学药理学和生理学系在R00阶段将解决的目标。目前可用的抗抑郁药在治疗重度抑郁障碍(MDD)方面存在严重的局限性，包括应答率低，大量的治疗耐药患者，以及在出现治疗反应之前的一段时间。值得注意的是，氯胺酮是一种NMDA受体阻滞剂，由于其快速而持久的抗抑郁作用，在临床试验中表现出了良好的前景。尽管其作用机制尚不清楚，但我们以前的研究表明，氯胺酮首先抑制皮质GABA中间神经元，导致兴奋性锥体神经元的去抑制，然后产生谷氨酸爆发，导致突触可塑性和快速的抗抑郁反应。然而，氯胺酮的作用似乎比简单的谷氨酸功能增强更为复杂，因为MDD受试者和应激动物在皮质脑区显示出强烈的GABA能缺陷，这种缺陷可以被氯胺酮治疗逆转。此外，通过包含α5的GABA受体(α5-GABA受体)靶向GABA系统的药物也被证明在啮齿动物中产生快速和持续的行为效应。因此，本项目的目标是扩展我们以前的工作，研究兴奋性和抑制性神经元机制如何相互作用来促进α介导的可塑性，最终导致氯胺酮诱导的行为反应，并探索与MDD治疗相关的其他GABA能化合物，包括GABA 5-GABA调节剂。候选人将测试这一新的假设，即除了谷氨酸诱导的可塑性外，内侧前额叶皮质(MPFC)中GABA功能的增加，特别是通过α5-GABA受体，对快速作用的抗抑郁药物的突触和行为效应至关重要。这一假设将通过整合多个层次的分析来进行研究，包括药理学、分子、遗传、行为和电路水平的方法。该实验室将致力于以下目标：1)研究参与α5-GABAAR NAM和PAM行为行为的细胞和突触机制；2)研究α5GABAAR在调节mPFC中特定细胞类型的神经元活动和相关行为结果中的作用。除了在理解抑郁症的病理生理学方面取得重大科学进展外，该项目还将指导开发治疗MDD的新一代药物的努力。

This project describes the aims that will be addressed during the R00 phase in the Department of Pharmacology and Physiology at the University of Rochester. Currently available antidepressants have serious limitations for treating major depressive disorder (MDD), including low response rates, a significant number of treatment resistant patients, and a time-lag before there is a therapeutic response. Notably, ketamine, an NMDA receptor blocker, has demonstrated promise in clinical trials because of its rapid and sustained antidepressant effects. Although its mechanisms of action are still to be elucidated, our previous studies suggest that ketamine first inhibits cortical GABA interneurons, leading to disinhibition of excitatory pyramidal neurons, and subsequently, a glutamate burst, which results in synaptic plasticity and fast antidepressant responses. However, the effects of ketamine seem to be more complex than a simple enhancement of glutamatergic function, since MDD subjects and stressed animals show robust GABAergic deficits in cortical brain areas, which can be reversed by ketamine treatment. In addition, drugs that target the GABA system via α5-containing GABAA receptors (α5-GABAAR) have also been shown to produce fast and sustained behavioral effects in rodents. Therefore, the goal of this project is to extend our previous work and investigate how excitatory and inhibitory neuronal mechanisms interact to promote GABA-mediated plasticity that culminates in ketamine-induced behavioral responses, and explore additional GABAergic compounds relevant to MDD treatment, including α5-GABAAR modulators. The candidate will test the novel hypothesis that, in addition to glutamate-induced plasticity, increased GABA function in the medial prefrontal cortex (mPFC), specifically through α5-GABAAR, is critical for the synaptic and behavioral effects of fast-acting antidepressants. This hypothesis will be investigated by integrating multiple levels of analysis, including pharmacological, molecular, genetic, behavioral and circuit-level approaches. The lab will address the following aims: 1) To investigate cellular and synaptic mechanisms involved in the behavioral actions of α5-GABAAR NAMs and PAMs and, 2) To investigate the role of α5GABAAR in mediating cell type-specific neuronal activity in the mPFC and associated behavioral outcomes. In addition to significant scientific advances in understanding the pathophysiology of depression, this project will guide efforts to develop a new generation of agents to treat MDD.