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Modeling Anti-NMDAR1 Autoantibodies in Psychiatric Disorders

精神疾病中抗 NMDAR1 自身抗体的建模

基本信息

批准号：
10039278
负责人：
XIANJIN ZHOU
金额：
$ 43.39万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10039278
关键词：
Active Immunization Address Amyloid beta-Protein Antibodies Antibody Specificity Antigens Anxiety Autoantibodies Autoimmunity Autopsy B-Lymphocytes Behavioral Binding Biological Assay Bioluminescence Blood Blood - brain barrier anatomy Blood capillaries Brain Brain region C-terminal Cells Cerebrospinal Fluid Cerebrovascular system Chimeric Proteins Chronic Clinical Clustered Regularly Interspaced Short Palindromic Repeats Cues DLG4 gene Disease Drainage procedure Encephalitis Exhibits Exposure to Extinction (Psychology)Fever Fright Gene Proteins Headache Human Image Immunization Immunoglobulin G Impairment In Vitro Infiltration Inflammation Intraperitoneal Injections Knock-in Link Long-Term Effects Luc Gene Luciferases Mental Health Mental disorders Modeling Molecular Molecular Analysis Monitor Motor Activity Mus NMDA receptor A1 PTPRC gene Pathogenesis Patients Peptides Peripheral Phagocytosis Phenotype Play Population Post-Traumatic Stress Disorders Prefrontal Cortex Production Proteins Psychotic Disorders Risk Factors Rodent Role Schizophrenia Senile Plaques Structure Structure of choroid plexus Symptoms Synapses T-Lymphocyte Transgenic Mice Tumor-infiltrating immune cells autism spectrum disorder base blood cerebrospinal fluid barrier blood-brain barrier crossing brain parenchyma density endophenotype fear memory frontal lobe fusion gene in vivo in vivo imaging learning extinction mouse model neuroinflammation neurotransmission prepulse inhibition psychiatric symptom success transcytosis

项目摘要

Project Summary High titers of autoantibodies against synaptic protein NMDAR1 have been demonstrated to cause anti- NMDAR1 encephalitis that exhibits psychosis, fear, anxiety, and other psychiatric symptoms. However, long- term effects of lower titers of anti-NMDAR1 autoantibodies on mental health are unknown, despite that ~5-10% of human population carries low titers of anti-NMDAR1 autoantibodies in their blood. We successfully generated modeling mice carrying low titers of anti-NMDAR1 autoantibodies. Mice carrying the anti-NMDAR1 autoantibodies for many months are healthy, and displayed no behavioral abnormalities except severe deficits in cued fear extinction learning (p=7.80x10-14, effect size: 2.57, power: 0.99) and recall of fear extinction (p=2.29x10-10, effect size: 1.65, power: 0.83), indicating that NMDAR functions may be impaired by the autoantibodies in prefrontal cortex. Impaired fear extinction and recall are clinical endophenotypes for many psychiatric disorders including PTSD, anxiety, schizophrenia, and autism. Peripheral circulating antibodies are largely blocked from entering brain by blood brain barriers (BBB) or blood CSF barriers (BCSFB). However, ~0.1% of blood circulating antibodies can cross these barriers into brain in healthy rodents and humans regardless of antibody specificities. It is conceivable that chronic low titers of circulating anti-NMDAR1 autoantibodies in our preliminary studies could disrupt NMDAR neurotransmission in mouse prefrontal cortex after crossing BBB and BCSFB. Frontal cortex is one of the brain regions innervated with the highest density of blood capillaries, indicating a potential of more influx of circulating anti-NMDAR1 autoantibodies in this region. Since prefrontal cortex plays a central role in the pathogenesis of psychiatric disorders, we hypothesize that prefrontal cortex is particularly vulnerable to chronic presence of low titers of anti-NMDAR1 autoantibodies, and neuroinflammation can exacerbate existing mild NMDAR1 autoimmunity to develop anti- NMDAR1 encephalitis-like phenotypes. In Aim1, we propose to generate mice carrying NMDAR1-Luc2 fusion gene using CRISPR to conduct longitudinal in vivo bioluminescence live imaging (BLI) of NMDAR1 proteins in mouse brain. We expect that NMDAR1-Luc2 proteins will be preferentially reduced in prefrontal cortex by chronic influx of anti-NMDAR1 autoantibodies in mice carrying low titers of anti-NMDAR1 autoantibodies. In Aim2, we will investigate whether systemic inflammation and neuroinflammation may exacerbate existing mild NMDAR1 autoimmunity to develop anti-NMDAR1 encephalitis-like phenotypes. Success of Aim1 will establish a potential mechanistic link between chronic low titers of anti-NMDAR1 autoantibodies that are common in human population and prefrontal cortex in the pathogenesis of a variety of psychiatric disorders. Success of Aim2 will provide evidence supporting that anti-NMDAR1 autoimmunity may be a spectrum of disorders from mild psychiatric disorders to severe anti-NMDAR1 encephalitis.

项目摘要针对突触蛋白NMDAR 1的高滴度自身抗体已被证明可引起抗NMDAR 1抗体。表现出精神病、恐惧、焦虑和其他精神症状的NMDAR 1脑炎。然而，长期以来- 抗NMDAR 1自身抗体的较低滴度对心理健康的长期影响尚不清楚，尽管约5-10%的人患有NMDAR 1自身抗体。的人群在其血液中携带低滴度的抗NMDAR 1自身抗体。我们成功产生携带低滴度抗NMDAR 1自身抗体的模型小鼠。携带抗NMDAR 1的小鼠许多个月的自身抗体是健康的，除了严重的缺陷外，没有表现出行为异常提示性恐惧消退学习（p=7.80x10-14，效应量：2.57，power：0.99）和恐惧消退回忆（p=2.29x10-10，效应量：1.65，把握度：0.83），表明NMDAR功能可能受到前额叶皮质中的自身抗体恐惧消退和回忆受损是许多人的临床内表型。精神障碍，包括创伤后应激障碍、焦虑症、精神分裂症和自闭症。外周循环抗体是在很大程度上被血脑屏障（BBB）或血CSF屏障（BCSFB）阻止进入脑。然而，在这方面，在健康啮齿动物和人类中，约0.1%的血液循环抗体可以穿过这些屏障进入大脑而不管抗体的特异性。可以想象，循环抗NMDAR 1的慢性低滴度在我们的初步研究中，自身抗体可以破坏小鼠前额叶皮层的NMDAR神经传递在穿过BBB和BCSFB之后。额叶皮层是脑内神经支配密度最高的区域之一的毛细血管，表明在这种情况下，可能会有更多的循环抗NMDAR 1自身抗体流入。地区由于前额叶皮质在精神疾病的发病机制中发挥着核心作用，我们假设前额叶皮层特别容易受到低滴度抗NMDAR 1长期存在的影响自身抗体和神经炎症可以加剧现有的轻度NMDAR 1自身免疫，从而产生抗NMDAR 1抗体。 NMDAR 1脑炎样表型。在Aim 1中，我们提出产生携带NMDAR 1-Luc 2融合的小鼠基因使用CRISPR进行NMDAR 1蛋白的纵向体内生物发光活体成像（BLI），老鼠的大脑我们预计，NMDAR 1-Luc 2蛋白将优先减少前额叶皮层，携带低滴度抗NMDAR 1自身抗体的小鼠中抗NMDAR 1自身抗体的慢性流入。在目的2，我们将调查是否全身炎症和神经炎症可能加剧现有的轻度 NMDAR 1自身免疫发展成抗NMDAR 1脑炎样表型。目标1的成功将建立慢性低滴度抗NMDAR 1自身抗体之间的潜在机制联系，人类和前额叶皮层在各种精神疾病的发病机制。成功 Aim 2将提供证据支持抗NMDAR 1自身免疫可能是一系列疾病，轻度精神障碍至重度抗NMDAR 1脑炎。