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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要目前可用的抗抑郁药在治疗重度抑郁症（MDD）方面存在严重局限性，包括反应率低、大量治疗耐药患者以及出现时间滞后值得注意的是，氯胺酮（一种 NMDA 受体阻滞剂）在临床上已显示出良好的前景。由于其快速和持续的抗抑郁作用，尽管其作用机制仍有待研究。阐明，我们之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，随后谷氨酸爆发，导致突触可塑性和快速抗抑郁反应然而，氯胺酮的作用似乎比氯胺酮更复杂。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强大的大脑皮层区域的 GABA 能缺陷可以通过氯胺酮治疗来逆转。通过含有 α5 的 GABAA 受体 (α5-GABAAR) 靶向 GABA 系统也被证明可以产生因此，该项目的目标是扩展我们之前的工作。并研究兴奋性和抑制性神经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诱导的行为反应，并探索其他 GABA 能化合物与 MDD 治疗相关的药物，包括 α5-GABAAR 调节剂，我们还将检验这一新假设。对于谷氨酸诱导的可塑性，增加内侧前额皮质 (mPFC) 中的 GABA 功能对于速效抗抑郁药对突触和行为的影响将通过整合来研究。多层次分析，包括药理学、分子、遗传、行为和电生理学我们将实现以下目标：1）表征神经编码和潜在的 GABAergic。 mPFC 中参与氯胺酮作用的机制与其抗抑郁功效相关，2) 研究参与 α5-GABAAR NAM 和 PAM 行为作用的电生理和突触机制，3) 研究 α5-GABAAR 在不同疾病中的作用介导神经元亚群 mPFC 中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抑郁症方面取得了重大科学进展外，潜在的新型抗抑郁药物，这项 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是在 Marina Picciotto 博士的指导下完成的。在 George Dragoi 和顾问委员会（Taylor 博士和 DiLeone 博士）的指导下，Fogaça 博士将收购对清醒、有行为能力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，结合她的一系列技术技能，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资助。