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.

项目摘要已经证明，针对突触蛋白NMDAR1的自身抗体的高滴度已被证明引起抗 NMDAR1脑炎表现出精神病，恐惧，焦虑和其他精神病症状。但是，长期抗NMDAR1自身抗体对心理健康的较低滴度的术语影响尚不清楚，尽管大约5-10％人口的血液中抗NMDAR1自身抗体的滴度低。我们成功产生的抗NMDAR1自身抗体的较低滴度的建模小鼠。携带抗NMDAR1的小鼠自身抗体已有多个月健康，除了严重缺陷以外，没有行为异常在提示恐惧灭绝学习中（p = 2.29x10-10，效果大小：1.65，功率：0.83），表明NMDAR功能可能会受到损害前额叶皮层中的自身抗体。恐惧灭绝和召回受损是许多人的临床内表型精神病，包括PTSD，焦虑，精神分裂症和自闭症。外围循环抗体是在很大程度上被血液脑屏障（BBB）或血液CSF屏障（BCSFB）进入大脑。然而，〜0.1％的血液循环抗体可以在健康的啮齿动物和人类中跨越这些障碍物无论抗体特异性如何。可以想象，循环抗NMDAR1的慢性低滴度我们的初步研究中的自身抗体可能会破坏鼠标前额叶皮层中的NMDAR神经传递越过BBB和BCSFB后。额叶皮层是具有最高密度支配的大脑区域之一血液毛细血管，表明有可能更多的循环抗NMDAR1自身抗体涌入地区。由于前额叶皮层在精神疾病的发病机理中起着核心作用，因此我们假设前额叶皮层特别容易受到抗NMDAR1的长期存在自身抗体和神经炎症会加剧现有的轻度NMDAR1自身免疫性 NMDAR1脑炎样表型。在AIM1中，我们建议生成携带NMDAR1-LUC2融合的小鼠基因使用CRISPR进行NMDAR1蛋白的纵向生物发光现场成像（BLI）小鼠大脑。我们预计NMDAR1-LUC2蛋白会优先降低前额叶皮层的抗NMDAR1自身抗体较低的小鼠中抗NMDAR1自身抗体的慢性涌入。在 AIM2，我们将调查系统性炎症和神经炎症是否会加剧现有的轻度 NMDAR1自身免疫性发展抗NMDAR1脑炎表型。 AIM1的成功将建立抗NMDAR1自身抗体的慢性低滴度与常见各种精神疾病的发病机理中的人群和前额叶皮层。成功 AIM2将提供证据，支持抗NMDAR1自身免疫可能是来自严重抗NMDAR1脑炎的轻度精神疾病。