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 阶段要解决的目标，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、治疗效果不佳等。值得注意的是，氯胺酮（一种 NMDA 受体阻滞剂）因其快速且持续的抗抑郁作用而在临床试验中具有前景。其作用仍有待阐明，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去抑制，随后导致谷氨酸爆发，从而导致突触可塑性和快速抗抑郁反应。氯胺酮似乎比简单地增强谷氨酸能功能更复杂，因为 MDD 受试者和应激动物在皮质大脑区域表现出强烈的 GABA 能缺陷，这可以此外，通过含α5的GABAA受体（α5-GABAAR）靶向GABA系统的药物也被证明可以在啮齿动物中快速产生和持续的行为效应，因此，该项目的目标是扩展。我们之前的工作以及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，研究和探索与 MDD 治疗相关的其他 GABA 能化合物，包括α5-GABAAR 调节剂将测试新的假设，即除了谷氨酸诱导的可塑性外，内侧前额叶皮层 (mPFC) 中 GABA 功能的增强（特别是通过 α5-GABAAR）对于快速运动的突触和行为效应至关重要。 - 抗抑郁药的作用。该假设将通过整合多个层面的分析进行研究，包括药理学、分子、遗传、行为和回路层面的方法：1）研究。参与 α5-GABAAR NAM 和 PAM 行为作用的细胞和突触机制，2) 除了在理解方面取得重大科学进展外，还研究 α5GABAAR 在介导 mPFC 中细胞类型特异性神经元活动中的作用。抑郁症的病理生理学，该项目将指导开发新一代治疗重度抑郁症的药物。