Synaptic autoimmunity in disorders of memory, behavior, cognition and psychosis

记忆、行为、认知和精神病障碍中的突触自身免疫

基本信息

批准号：
7940877
负责人：
RITA J. BALICE-GORDON
金额：
$ 49.42万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7940877
关键词：
AMPA Receptors Acute Address Affect Aggressive behavior Agitation Amnestic Disorder Antibodies Antigen Targeting Antigens Anxiety Area Autistic Disorder Autoantigens Autoimmune Process Autoimmune Responses Autoimmunity Autonomic Dysfunction Behavior Behavior Disorders Behavioral Behavioral Mechanisms Binding Brain Catatonia Cell Adhesion Molecules Cell surface Cerebrospinal Fluid Child Clinical Cognition Cognitive deficits Culture Media Dendrites Diagnosis Diagnostic tests Disease Dyskinetic syndrome Electroencephalography Encephalopathies Epilepsy Etiology Excision Family Functional disorder Glutamate Receptor Hippocampus (Brain)Human Immune Immune response In Vitro Individual Inflammatory Institution Intensive Care Laboratories Language Language Disorders Lead Learning Mediating Membrane Memory Memory Disorders Memory impairment Methods Molecular Mutism N-Methyl-D-Aspartate Receptors NR1 NMDA receptor Nerve Tissue Neurology Neurons Neurotransmitter Receptor Ovarian Teratoma Patients Personality Play Presynaptic Terminals Prevention Process Proteins Psychotic Disorders Public Health Publishing Reporting Research Rodent Role Schizophrenia Seizures Site Structure Synapses Synaptic Transmission Synaptic plasticity Syndrome Techniques Testing Therapeutic Intervention Woman Work cancer therapy density hippocampal pyramidal neuron in vivo insight member neural circuit neuronal survival neuropsychiatry neurotransmission novel postsynaptic public health relevance receptor research study synaptic function tumor ward young adult

项目摘要

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (01): Behavior, Behavioral Change, and Prevention and specific Challenge Topic 01-AA-102: Functional Roles of Neuroimmune Factors in Mediating Behavior. The focus of this proposal is the characterization of autoimmune responses to synaptic proteins that result in disorders of behavior, memory, cognition and psychosis. In 2007, we first reported a group of young women who acutely developed psychotic behavior or schizophrenia, subsequently followed by decrease of memory, catatonia, abnormal movements, and autonomic dysfunction. Using techniques that we optimized to detect antibodies to neuronal cell surface and/or synaptic proteins, we found that all patients had antibodies against the NR1 subunit of the NMDA receptor, a glutamate receptor that plays important roles in synaptic transmission and plasticity. In about 60% of patients, the immune trigger was an ovarian teratoma with ectopic nervous tissue and expressed NMDAR. Since that report, the number of patients diagnosed with this disorder has rapidly increased, and similar strategies applied to patients with other neuropsychiatric manifestations have led to the discovery of 4 novel immune responses to cell surface/synaptic autoantigens, including, among others, the GluR1/2 subunits of the AMPA receptor, and the GABA(B1) receptor. Our recently published studies have shown that patients' NMDAR or AMPAR antibodies reduce the number and synaptic localization of receptor clusters in dissociated hippocampal neurons in vitro, and that these effects are reversed upon removal of antibodies from the culture medium. These findings have led to the hypothesis that many acute encephalopathies of unknown etiology causing behavioral, personality and memory deficits are likely mediated by antibodies that affect neurotransmitter receptors at cell surface or synaptic sites. In 3 disorders for which preliminary studies show CSF antibodies to cell surface/synaptic proteins, including rapidly progressive psychosis; acute behavioral deficits, language dysfunction and mutism in children; and acute memory deficits and anterograde amnestic syndromes, we will perform 2 aims: 1) Determine the identity of the autoantigens in these 3 disorders, using modified highly sensitive methods to detect the presence of antibodies to neuronal cell surface/synaptic antigens; and 2) Determine how patients' antibodies modify the structure and function of synapses in rodent neurons in vitro and in vivo, focusing on how the density and synaptic localization of antigens is altered by patients' antibodies, and how these recover after antibodies are removed. The results of these experiments will allow us to begin to determine the range of autoantigens that lead to encephalopathies with associated behavioral manifestations in humans, and to begin to determine the underlying molecular, cellular and synaptic mechanisms in these common and devastating disorders. We propose to screen patients presenting with encephalopathies of unknown etiology that result in personality, behavior and language dysfunction for autoimmune processes. We hypothesize that patient antibodies affect neurotransmitter receptors in the neuronal membrane and at synapses, leading to changes in synaptic and circuit function that in turn lead to behavioral, personality and memory deficits. The results of the proposed experiments will provide fundamentally new insights into the molecular, cellular, synaptic and behavioral mechanisms underlying anti-glutamate receptor encephalopathies, provide new insights into memory and cognitive deficits that are hallmarks of these disorders, and potentially suggest avenues for therapeutic intervention in these common and devastating disorders of memory and cognition that have a significant public health impact. PUBLIC HEALTH RELEVANCE: We propose to screen patients presenting with encephalopathies of unknown etiology that result in personality, behavior and language dysfunction for autoimmune processes. We hypothesize that patient antibodies affect neurotransmitter receptors in the neuronal membrane and at synapses, leading to changes in synaptic and circuit function that in turn lead to behavioral, personality and memory deficits. The results of the proposed experiments will provide fundamentally new insights into the molecular, cellular, synaptic and behavioral mechanisms underlying anti-glutamate receptor encephalopathies, provide new insights into memory and cognitive deficits that are hallmarks of these disorders, and potentially suggest avenues for therapeutic intervention in these common and devastating disorders of memory and cognition that have a significant public health impact.

描述（由申请人提供）：此申请解决广泛的挑战领域（01）：行为，行为改变以及预防和特定挑战主题01-AA-102：神经免疫因子在中介行为中的功能作用。该提案的重点是对突触蛋白的自身免疫反应的表征，这些反应会导致行为，记忆，认知和精神病的疾病。 2007年，我们首先报道了一群年轻女性，她们急性发展精神病行为或精神分裂症，随后记忆力下降，卡塔托尼亚，异常运动和自主功能障碍。使用我们优化的技术来检测对神经元细胞表面和/或突触蛋白的抗体，我们发现所有患者均对NMDA受体的NR1亚基均抗体，NMDA受体的NR1亚基，谷氨酸受体是一种在突触传播和可塑性中起重要作用的谷氨酸受体。在约60％的患者中，免疫触发是一种卵巢畸胎瘤，具有异位神经组织并表达NMDAR。自从该报告以来，被诊断患有这种疾病的患者数量迅速增加，并且适用于其他神经精神上表现的患者的类似策略导致发现了4种对细胞表面/突触自动抗体的免疫反应，包括AMPA受体和GABA（b1）受体的GLUR1/2亚基。我们最近发表的研究表明，患者的NMDAR或AMPAR抗体减少了分离的海马神经元中受体簇的数量和突触定位，并且在从培养基中去除抗体后，这些作用会逆转。这些发现导致了以下假设：许多未知病因的急性脑病导致行为，人格和记忆缺陷可能是由影响细胞表面或突触部位神经递质受体受体的抗体介导的。在三种疾病中，初步研究表明了对细胞表面/突触蛋白的CSF抗体，包括快速进行性心理学；儿童的急性行为缺陷，语言功能障碍和突变；以及急性记忆缺陷和朝天障碍综合症，我们将执行2个目的：1）确定这三种疾病中自身抗原的同一性，使用改良的高敏感方法检测对神经元细胞表面/突触抗原的抗体的存在； 2）确定患者的抗体如何在体外和体内修改啮齿动物神经元突触的结构和功能，重点关注患者抗体的密度和突触定位如何改变抗原的密度和突触定位，以及在去除抗体后它们如何恢复。这些实验的结果将使我们能够开始确定导致脑病的自身抗原范围与人类相关的行为表现，并开始确定这些常见和破坏性疾病的基本分子，细胞和突触机制。我们建议筛选出患有未知病因的脑病的患者，这些脑病会导致自身免疫过程的性格，行为和语言功能障碍。我们假设患者抗体会影响神经元膜和突触时的神经递质受体，从而导致突触和电路功能的变化，进而导致行为，人格和记忆缺陷。提出的实验的结果将提供有关分子，细胞，突触和行为机制的基本新见解影响。公共卫生相关性：我们建议筛查患者出现未知病因的脑病，这些脑病会导致自身免疫过程的性格，行为和语言功能障碍。我们假设患者抗体会影响神经元膜和突触时的神经递质受体，从而导致突触和电路功能的变化，进而导致行为，人格和记忆缺陷。提出的实验的结果将提供有关分子，细胞，突触和行为机制的基本新见解影响。