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: 10778687
• 负责人: Manoela Fogaca
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF ROCHESTER
• 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 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10778687
• 关键词: Address; Aftercare; Animals; Antidepressive Agents; Area; Behavioral; Brain; Calcium; Clinical; Clinical Trials; Complex; Data; Development; Disinhibition; Drug Targeting; Equilibrium; Functional disorder; Future; Generations; Genetic; Glutamates; Goals; Interneurons; Investigation; Ketamine; Literature; Major Depressive Disorder; Medial; Mediating; Mental Depression; Molecular; N-Methyl-D-Aspartate Receptors; Neurons; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Physiology; Prefrontal Cortex; Protein Biochemistry; Protein Biosynthesis; Resistance; Rodent; Role; Scientific Advances and Accomplishments; Signal Transduction; Stress; Synapses; Synaptic plasticity; System; Testing; Time; Translations; Universities; Vertebral column; Work; abuse liability; antidepressant effect; behavioral outcome; behavioral response; calmodulin-dependent protein kinase II; cell type; density; excitatory neuron; gamma-Aminobutyric Acid; genetic approach; glutamatergic signaling; hippocampal pyramidal neuron; in vivo; inhibitory neuron; knock-down; neural circuit; novel; novel therapeutics; pharmacologic; preclinical study; receptor; receptor function; response; side effect; synaptogenesis; translational study; treatment response

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.

该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对治疗重度抑郁症（MDD）有严重的局限性，包括低反应率，大量的抗治疗患者以及在患有治疗反应之前的时间滞后。值得注意的是，NMDA受体阻滞剂氯胺酮由于其快速且持续的抗抑郁作用而在临床试验中表现出了希望。尽管其作用机制仍尚待阐明，但我们先前的研究表明，氯胺酮首先抑制皮质GABA中间神经元，从而导致对兴奋性金字塔神经元的抑制作用，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对谷氨酸能功能的简单增强更为复杂，因为MDD受试者和压力动物在皮质大脑区域表现出强大的GABA能定义，可以通过氯胺酮治疗来逆转。此外，还显示通过含α5的GABAA受体（α5-Gabaar）靶向GABA系统的药物也已显示出在啮齿动物中产生快速持续的行为效应。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，从而在氯胺酮诱导的行为反应中达到顶点，并探索与MDD治疗相关的其他GABA能化合物，包括α5-Gabaar调节剂。候选人将检验一个新的假设，即除了谷氨酸诱导的可塑性外，还提高了培养基前额叶皮层（MPFC）的GABA功能，特别是通过α5-Gabaar，对于快速作用抗抑郁药的突触和行为效应至关重要。该假设将通过整合多个分析，包括药物，分子，遗传，行为和电路级方法来研究。该实验室将解决以下目的：1）研究参与α5-GABAAR NAM和PAM行为作用的细胞和突触机制，以及2）研究α5GABAAR在介导细胞类型特异性神经元活性在MPFC和相关行为结果中的作用。除了了解抑郁症的病理生理学方面的显着科学进步外，该项目还将指导开发新一代药物治疗MDD的努力。