Cell-type and sex-specific organization and neurexin-3 utilization at parvalbumin inhibitory synapses in ventral subiculum

腹侧下托小清蛋白抑制突触的细胞类型和性别特异性组织以及神经素 3 的利用

• 批准号: 10464883
• 负责人: Emma E Boxer
• 金额: $ 0.98万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-04 至 2022-11-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10464883
• 关键词: Acute; Alternative Splicing; Animal Model; Architecture; Behavior; Brain; Brain region; Cell Adhesion Molecules; Cells; Communication; Control Animal; Coupled; Data; Disease; Electrophysiology (science); Elements; Epilepsy; Etiology; Exhibits; Family; Female; Fright; Functional disorder; Genes; Hippocampus (Brain); Human; Hyperactivity; Impairment; Individual; Infection; Inhibitory Synapse; Injections; Interneurons; Lead; Learning; Light; Link; Measures; Mediating; Memory; Mental Depression; Microscopy; Molecular; Molecular Biology; Morphology; Mus; Mutation; Myoepithelial cell; Nature; Neurons; Output; Parvalbumins; Patients; Pattern; Phenotype; Play; Property; Protein Isoforms; Regulation; Rewards; Role; Schizophrenia; Sex Differences; Shapes; Signal Transduction; Slice; Specific qualifier value; Stress; Structure; Synapses; Synaptic Transmission; Testing; Training; Vertebrates; Viral; addiction; autism spectrum disorder; base; cell type; dimorphism; experimental study; hippocampal subregions; in vivo; information processing; inhibitory neuron; interdisciplinary approach; male; mouse genetics; mouse model; mutant; nervous system disorder; neuropsychiatric disorder; novel; optogenetics; postsynaptic; presynaptic; reward processing; sex; sexual dimorphism; stress disorder; synaptic function; transmission process; vector control

Project Summary The ventral subiculum (vSUB) is the major output structure of the ventral hippocampus and plays an integral role in the regulation of stress, fear and reward processing. Hyperactivity of vSUB is a pathophysiology common to schizophrenia and addiction disorders and is proposed to arise from reduced local inhibition onto vSUB principle neurons, identified as burst and regular spiking neurons, which engage in parallel information processing circuits. There is evidence from human patients and mouse models that inhibitory parvalbumin basket cells (PVs) in vSUB are specifically disrupted in schizophrenia. PVs are a prominent class of interneurons that provide potent inhibition of principle neurons. Despite the obvious importance of vSUB PVs to normal function and their relevance to disease, very little is known about the fundamental connectivity, properties of synaptic transmission, or molecules that govern synapses made by PV interneurons onto regular and burst spiking principle neurons of vSUB. Additionally, although sex differences in schizophrenia, addiction, and stress have been described for decades, little is known about underlying sex differences within brain regions associated with these diseases, such as vSUB. Neurexin-3 (Nrxn3), an evolutionarily conserved and essential presynaptic adhesion molecule, may exert dominant and potentially distinct control of PV synaptic properties in vSUB. Neurexins are critical for synapse specification and synaptic transmission, and Nrxn3 exhibits diverse brain region, cell type, and synapse specific functions. Notably, mutations in Nrxn3 have been repeatedly linked to schizophrenia and addiction and Nrxn3 is robustly and uniquely expressed in hippocampal PVs, indicating it plays a critical role at vSUB PV synapses and may contribute to the etiologies that underlie these disorders. The specific function(s) of Nrxn3 at PV synapses, however, has surprisingly never been described. Supported by strong preliminary data, here, I will provide a comprehensive interrogation of the cell-type- and sex-specific wiring, synaptic transmission and usage of Nrxn3 by PVs among regular and burst spiking cells in vSUB. I will employ a multi-disciplinary approach consisting of mouse genetics, viral injections, optogenetics, and molecular replacement together with electrophysiology in acute vSUB slices to assess 1) the specific function(s) of Nrxn3 at PV-regular spiking and PV-burst spiking cell synapses of male and female mice and 2) the specific Nrxn3 isoforms and domains required to regulate these functions. This project will expand our understanding of the functional organization and molecular constituents that shape inhibition within a brain region associated with schizophrenia, addiction, and stress disorders.

项目摘要 腹侧亚核(VSUB)是腹侧海马的主要输出结构，起着不可或缺的作用 在调节压力、恐惧和奖励的过程中。VSUB的过度活动是一种常见的病理生理学 精神分裂症和成瘾障碍，并被认为是由于vSUB原理引起的局部抑制减少 神经元，被认为是突发性和规律性的尖峰神经元，参与并行的信息处理电路。 来自人类患者和小鼠模型的证据表明，抑制小白蛋白篮子细胞(PV)在 VSUB在精神分裂症中尤其受到干扰。室旁核是一类重要的中间神经元，它为 主神经元的抑制。尽管vSUB PV对正常功能和它们的 与疾病的相关性，对基本的连通性，突触传递的特性， 或控制由PV中间神经元形成的突触到规则和爆发式放电原理神经元的分子 VSuB。此外，尽管在精神分裂症、成瘾和压力方面的性别差异已经被描述为 几十年来，人们对与这些疾病相关的大脑区域潜在的性别差异知之甚少， 例如vSUB。Neuresin-3(NRXN3)是一种进化上保守且必需的突触前黏附分子， 可能对vSUB中的PV突触特性发挥主导的和潜在的不同控制作用。Neurexins对于 突触规范和突触传递，NRXN3表现出不同的脑区、细胞类型和突触 具体功能。值得注意的是，NRXN3的突变一再被认为与精神分裂症和成瘾有关，而且 NRXN3在海马室强而独特地表达，表明它在vSUB室起关键作用。 突触，并可能有助于这些疾病的病因。NRXN3的特殊功能(S) 然而，令人惊讶的是，PV突触从未被描述过。 在强大的初步数据的支持下，在这里，我将提供一个全面的细胞类型-和 正常和爆发性棘细胞之间的性别特异性连接、突触传递和PVs对NRXN3的利用 VSuB。我将采用一种多学科的方法，包括小鼠遗传学，病毒注射，光遗传学， 在急性vSUB切片中进行分子置换和电生理检查，以评估1)特异性 NRXN3在雌雄小鼠PV规则棘波和PV爆发棘细胞突触中的作用(S) 调节这些功能所需的特定NRXN3亚型和结构域。这个项目将扩大我们的 了解在大脑区域内形成抑制的功能组织和分子成分 与精神分裂症、成瘾和应激障碍有关。