Cortical GABAergic mechanisms underlying rapid and sustained antidepressant responses

皮质 GABA 能机制是快速和持续抗抑郁反应的基础

• 批准号: 10370708
• 负责人: Manoela Fogaca
• 金额: $ 10.2万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10370708
• 关键词: Academic skills; Address; Advisory Committees; Aftercare; Animals; Antidepressive Agents; Area; Behavior; Behavioral; Brain; Cells; Clinical; Clinical Trials; Code; Complex; Data; Development; Disinhibition; Drug Targeting; Electrophysiology (science); Equilibrium; Functional disorder; Funding; Future; Generations; Glutamates; Goals; Interneurons; Investigation; Ketamine; Laboratory Research; Major Depressive Disorder; Medial; Mediating; Mental Depression; Mentors; Mentorship; Molecular Biology; Molecular Genetics; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurons; Patients; Pattern; Pharmaceutical Preparations; Pharmacology; Phase; Population; Prefrontal Cortex; Protein Biosynthesis; Proteins; Pyramidal Cells; Resistance; Rodent; Role; Scientific Advances and Accomplishments; Scientist; Scopolamine; Signal Transduction; Stress; Synapses; Synaptic plasticity; System; Technical Expertise; Testing; Time; Training; Translations; Work; antidepressant effect; awake; behavior test; behavioral outcome; behavioral response; calmodulin-dependent protein kinase II; career development; cell type; experimental study; gamma-Aminobutyric Acid; glutamatergic signaling; hippocampal pyramidal neuron; in vivo; knock-down; novel; novel therapeutics; preclinical study; professor; programs; receptor; recruit; relating to nervous system; response; skills; synaptogenesis; translational study; treatment response

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.

项目摘要 目前可用的抗抑郁药对治疗重度抑郁症（MDD）的严重局限性， 包括低反应率，大量的抗治疗患者以及在有时间段之前 治疗反应。值得注意的是，NMDA受体阻滞剂氯胺酮在临床上表现出了希望 由于其快速且持续的抗抑郁作用而进行的试验。尽管其行动机制仍然是 阐明的，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抑制作用，随后是谷氨酸爆发，导致突触 可塑性和快速抗抑郁反应。但是，氯胺酮的作用似乎比 谷氨酸能功能的简单增强，因为MDD受试者和压力动物表现强大 皮质大脑区域的GABA能防御，可以通过氯胺酮治疗逆转。另外，毒品 通过含α5的GABAA受体（α5-Gabaar）靶向GABA系统也已显示出来 啮齿动物的快速和持续行为影响。因此，该项目的目的是扩展我们以前的工作 并研究令人兴奋和抑制性的神经元机制如何相互作用以促进GABA介导的可塑性 最终导致氯胺酮引起的行为反应，并探索其他GABA能化合物 与MDD处理有关，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，培养基前额叶皮层（MPFC）中的GABA功能提高至关重要 快速作用抗抑郁药的突触和行为效应。该假设将通过整合来研究 多个分析，包括药物，分子，遗传，行为和电生理学 方法。我们将解决以下目的：1）表征神经编码和基础GABA能 MPFC中涉及氯胺酮与其抗抑郁药相关的作用的机制，2）研究参与α5-Gabaar NAM和PAMS和PAMS的TEH行为作用的电生理和合成机制，以及3）研究α5-GABAAR在不同神经元中的作用 MPFC和相关行为结果中的电生理反应。 除了理解抑郁症的病理生理学和识别的显着科学进步外 潜在的新型抗抑郁药，该K99提案将为Fogaça博士提供培训和心态 将提高她的技术和学术技能，使她成为一名独立学术科学家 她自己的研究实验室和计划。在Marina Picciotto博士的心态下，博士的同学 乔治·德拉多（George Dragoi）和咨询委员会的指导（泰勒（Taylor and Dileone）博士），Fogaça博士将获得 在醒着，行为小鼠和其他职业发展培训中进行电生理学的广泛培训， 结合她一系列技术技能，这将使她能够过渡到独立阶段 助理教授，并在R00阶段结束时申请R01资金。