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

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。然而，非常 关于它们活动的控制机制，人们知之甚少。具体地说，有一种迫切的需要 了解抑制性突触传入中间神经元的形成和维持。我们的长期合作 目的是更好地了解参与抑制控制的分子机制。 在皮质神经精神障碍中允许操纵突触抑制的神经元间活动 活动中断。总的目标是确定神经连接蛋白2(Nlgn2)在这一过程中的调节作用 并更好地了解Nlgn2的缺失如何改变抑制性中间神经元和导联的活动 为了疾病。中心假说是Nlgn2在抑制的调节中起重要作用。 GABA能中间神经元和中间神经元中Nlgn2的缺失导致皮层活动的功能后果 这可能会导致神经精神症状。生长抑素阳性中间神经元中Nlgn2的丢失 导致进入这些细胞的突触抑制输入的频率和幅度降低。目标一号意志 结合经典的突触生理学和药理学与输入特异的光遗传学来识别 导致SST中间神经元抑制性输入改变的突触机制。目标二将用于 活体钙成像和脑电(EEG)记录以确定高血压患者的功能后果 SST中间神经元中Nlgn2的丢失分别对细胞活动和整体皮质活动产生影响。这些 由于关键障碍，包括无法具体地 操纵中间神经元上的抑制性突触，以及无法直接测试和操纵 脑片电生理学中间神经元亚型之间的联系。这项建议克服了这些问题 由于一种利用病毒遗传学、Cre重组酶和FlpO重组酶的新方法造成的障碍，以及 Nlgn2的特殊操作，Nlgn2是一种突触后蛋白，专门发现于抑制性突触。建议数 这项研究有望阐明特定参与调节皮质的分子机制。 中间神经元活性。这一贡献将是重要的，因为它将允许操纵中间神经元 改变皮质抑制水平的活动，作为神经精神疾病的一种新的靶向治疗 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.