Cortical GABAergic mechanisms underlying rapid and sustained antidepressant responses

项目总结 目前可用的抗抑郁药在治疗严重抑郁障碍(MDD)方面具有严重限制， 包括低应答率，大量治疗耐药患者，以及在出现 一种治疗反应。值得注意的是，氯胺酮，一种Nmda受体阻滞剂，已经在临床上显示出希望。 试验，因为它的快速和持久的抗抑郁作用。尽管其作用机制仍有待于 我们先前的研究表明，氯胺酮首先抑制皮质GABA中间神经元，导致 兴奋性锥体神经元解除抑制，随后谷氨酸爆发，导致突触 可塑性和快速的抗抑郁反应。然而，氯胺酮的影响似乎比 谷氨酸能功能的简单增强，因为MDD受试者和应激动物表现出健壮 大脑皮质区域的GABA能缺陷，这可以通过氯胺酮治疗来逆转。此外，那些药物 通过含有α5的GABA受体(α5-GABA受体)靶向GABA系统也被证明能产生 对啮齿动物的快速和持续的行为影响。因此，这个项目的目标是扩展我们以前的工作 并研究兴奋性和抑制性神经元机制如何相互作用来促进GABA介导的可塑性 这最终导致了氯胺酮诱导的行为反应，并探索了其他GABA能化合物 与MDD治疗相关的药物，包括α5-GABAAR调节剂。我们将测试新的假设，此外， 对于谷氨酸诱导的可塑性，增加内侧前额叶皮质(MPFC)的GABA功能对于 速效抗抑郁药对突触和行为的影响。这一假说将通过整合 多层次分析，包括药理学、分子、遗传学、行为学和电生理学 接近了。我们将解决以下目标：1)表征神经编码和潜在的GABA能 2)研究α5-GABAAR NAMS和PAMS的电生理和突触机制；3)研究α5-GABAAR在不同神经元亚群中的作用。 MPFC的电生理反应和相关的行为结果。 除了在理解抑郁症的病理生理学和识别 潜在的新型抗抑郁药物，K99提案将为Fogaça博士提供培训和指导， 将提高她的技术和学术技能，为她成为一名独立的学术科学家做好准备 她自己的研究实验室和项目。在Marina Picciotto博士的指导下， 在乔治·德拉戈伊和一个咨询委员会(泰勒博士和迪里昂博士)的指导下，福加萨博士将获得 对清醒的、行为正常的小鼠进行广泛的电生理学培训，以及额外的职业发展培训， 这与她的一系列技术技能相结合，将使她具备过渡到独立阶段的能力 助理教授，并在R00阶段结束时申请R01资金。

PROJECT SUMMARY 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. We will test the novel hypothesis that, in addition to glutamate-induced plasticity, increased GABA function in the medial prefrontal cortex (mPFC) 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 electrophysiological approaches. We will address the following aims: 1) To characterize neural coding and the underlying GABAergic mechanisms in the mPFC involved in the actions of ketamine relevant to its antidepressant efficacy, 2) To investigate electrophysiological and synaptic mechanisms involved in teh behavioral actions of α5-GABAAR NAMs and PAMs and, 3) To investigate the role of α5-GABAAR in different neuronal subpopulations in mediating electrophysiological responses in the mPFC and associated behavioral outcomes. In addition to significant scientific advances in understanding the pathophysiology of depression and identifying potential novel antidepressant agents, this K99 proposal will provide training and mentorship for Dr. Fogaça that will increase her technical and academic skills, preparing her to become an independent academic scientist with her own research laboratory and program. Under the mentorship of Dr. Marina Picciotto, co-mentorship of Dr. George Dragoi and the guidance of an advisory committee (Drs. Taylor and DiLeone), Dr. Fogaça will acquire extensive training in electrophysiology in awake, behaving mice, and additional career development training, which in combination with her array of technical skills, will equip her to transition to the independent phase as an Assistant Professor, and to apply for R01 funding at the end of the R00 phase.