The role of Neuroligin 2 in the regulation of GABAergic interneuron activity and cortical inhibition

Neuroligin 2 在 GABA 能中间神经元活性和皮质抑制调节中的作用

• 批准号: 10399690
• 负责人: Colleen Michelle Brady
• 金额: $ 0.25万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10399690
• 关键词: Address; Cells; Cerebral cortex; Data; Disease; Electroencephalography; Electrophysiology (science); Enterobacteria phage P1 Cre recombinase; Family; Family member; Frequencies; Functional disorder; Future; Genetic; Goals; Image; Individual; Inhibitory Synapse; Interneurons; Knock-out; Knowledge; Lead; Maintenance; Mediating; Mission; Molecular; Mutation; Output; Pathogenesis; Pharmacology; Physiology; Play; Probability; Protein Family; Proteins; Public Health; Pyramidal Cells; Regulation; Research; Role; Schizophrenia; Shapes; Slice; Somatostatin; Symptoms; Synapses; Synaptic Membranes; System; Testing; Therapeutic; United States National Institutes of Health; Vasoactive Intestinal Peptide; Viral; autism spectrum disorder; base; cell type; genetic manipulation; in vivo; inhibitory neuron; insight; member; mouse model; neuroligin 2; neuropsychiatric disorder; neuropsychiatric symptom; neuroregulation; new therapeutic target; novel strategies; optogenetics; postsynaptic; presynaptic; recombinase; spatiotemporal; synaptic inhibition; targeted treatment; virus genetics

Project Summary/Abstract GABAergic interneurons are critical for the maintenance of proper levels of cortical excitability. However, very little is known about the mechanisms involved in the control of their activity. Specifically, there is a critical need to understand the formation and maintenance of inhibitory synaptic inputs onto interneurons. Our long-term goal is to gain a better understanding of the molecular mechanisms involved in the control of inhibitory interneuron activity to allow for manipulation of synaptic inhibition in neuropsychiatric disorders where cortical activity is disrupted. The overall goal is to determine the role of Neuroligin 2 (Nlgn2) in the regulation of this inhibition and to better understand how loss of Nlgn2 alters the activity of the inhibitory interneurons and leads to disease. The central hypothesis is that Nlgn2 plays an essential role in the regulation of inhibition onto GABAergic interneurons and loss of Nlgn2 in interneurons leads to functional consequences on cortical activity that may result in neuropsychiatric symptoms. Loss of Nlgn2 in somatostatin positive (Sst+) interneurons results in a decrease in the frequency and amplitude of synaptic inhibitory inputs onto those cells. Aim one will combine classical synaptic physiology and pharmacology with input-specific optogenetics to identify the synaptic mechanisms that lead to alterations in inhibitory inputs onto Sst+ interneurons. Aim two will use in vivo Ca2+ imaging and electroencephalography (EEG) recordings to determine the functional consequences of loss of Nlgn2 in Sst+ interneurons on both cellular activity and overall cortical activity, respectively. These important questions have yet to be addressed due to critical barriers including the inability to specifically manipulate inhibitory synapses onto interneurons and the inability to directly test and manipulate the connections between subtypes of interneurons in slice electrophysiology. This proposal overcomes these barriers due to a novel approach that utilizes viral genetics, Cre recombinase, and FlpO recombinase, and the specific manipulation of Nlgn2, a post-synaptic protein found exclusively at inhibitory synapses. The proposed research is expected to elucidate the molecular mechanisms involved specifically in the regulation of cortical interneuron activity. This contribution will be significant because it will allow for the manipulation of interneuron activity to alter levels of cortical inhibition, serving as a novel therapeutic target therapy for neuropsychiatric diseases in the future.

项目摘要/摘要 GABA能中间神经元对于维持适当水平的皮质兴奋性至关重要。但是，非常 关于其活性控制的机制知之甚少。具体来说，有急需 了解抑制性突触输入对中间神经元的形成和维持。我们的长期 目标是更好地了解抑制性控制的分子机制 中间神经元的活性允许在皮质疾病中操纵神经精神疾病的突触抑制作用 活动被中断。总体目标是确定神经素2（NLGN2）在调节中的作用 抑制作用并更好地了解NLGN2的损失如何改变抑制性中间神经元和铅的活性 疾病。中心假设是NLGN2在调节抑制作用中起着至关重要的作用 GABA能中间神经元和中间神经元中NLGN2的丧失会导致皮质活性的功能后果 这可能导致神经精神症状。生长抑素阳性（SST+）中间神经元中NLGN2的损失 导致突触抑制输入对这些细胞的频率和幅度降低。瞄准一个意志 将经典的突触生理学和药理学与投入特异性光遗传学结合起来，以识别 导致抑制性输入对SST+中间神经元的变化的突触机制。目标两个将使用 体内CA2+成像和脑电图（EEG）记录，以确定功能后果 SST+中间神经元在细胞活性和整体皮质活性中的NLGN2丧失。这些 由于关键障碍，包括无法具体的障碍，尚未解决重要的问题 操纵抑制性突触到中间神经元，无法直接测试和操纵 切片电生理学中神经元亚型之间的连接。该提议克服了这些建议 由于采用病毒遗传学，CRE重组酶和FLPO重组酶的新方法而引起的障碍，以及 NLGN2的特异性操纵是一种仅在抑制突触的突触后蛋白。提议 预计研究将阐明专门调节皮质的分子机制 内神经活动。这项贡献将是重要的，因为它将允许操纵中间神经元 改变皮质抑制水平的活性，是一种新型的神经精神治疗治疗疗法 将来的疾病。