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

项目概要/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。可是 对控制其活性的机制知之甚少。具体而言，迫切需要 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 目的是更好地了解参与抑制性细胞凋亡控制的分子机制。 中间神经元活动，以允许在神经精神疾病中操纵突触抑制， 活动中断。总的目标是确定神经连接素2（Nlgn 2）在这种调节中的作用。 为了更好地理解Nlgn 2的缺失如何改变抑制性中间神经元的活性， 疾病。中心假设是Nlgn 2在调节对细胞的抑制中起重要作用。 GABA能中间神经元和中间神经元中Nlgn 2的缺失导致对皮质活动的功能后果 可能导致神经精神症状生长抑素阳性（Sst+）中间神经元中Nlgn 2的丢失 导致对这些细胞的突触抑制性输入的频率和幅度降低。瞄准一个意志 联合收割机将经典突触生理学和药理学与输入特异性光遗传学相结合， 突触机制，导致Sst+中间神经元的抑制性输入的改变。目标二将用于 体内Ca 2+成像和脑电图（EEG）记录，以确定 Sst+中间神经元中Nlgn 2的损失分别对细胞活性和总体皮质活性两者的影响。这些 由于关键的障碍，包括无法具体地 操纵抑制性突触到中间神经元上，并且不能直接测试和操纵 切片电生理学中中间神经元亚型之间的联系。该提案克服了这些 由于利用病毒遗传学、Cre重组酶和FlpO重组酶的新方法， Nlgn 2的特异性操作，Nlgn 2是一种仅在抑制性突触处发现的突触后蛋白。拟议 这项研究有望阐明皮质神经元调控的分子机制， 中间神经元活动这一贡献将是重要的，因为它将允许操纵中间神经元， 活性，以改变皮层抑制水平，作为一种新的治疗靶点治疗神经精神疾病 未来的疾病

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.