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

• 批准号: 7814626
• 负责人: RITA J. BALICE-GORDON
• 金额: $ 47.12万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7814626
• 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

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)：本申请涉及广泛的挑战领域(01)：行为，行为改变，以及预防和特定挑战主题01-AA-102：神经免疫因子在调节行为中的功能作用。这项建议的重点是描述对突触蛋白的自身免疫反应，这些蛋白会导致行为、记忆、认知和精神障碍。2007年，我们首次报道了一组年轻女性，她们急性发展为精神病行为或精神分裂症，随后出现记忆力下降、紧张症、异常运动和自主神经功能障碍。使用我们优化的检测神经细胞表面和/或突触蛋白抗体的技术，我们发现所有患者都有针对NMDA受体NR1亚单位的抗体，NMDA受体是一种谷氨酸受体，在突触传递和可塑性中发挥重要作用。在大约60%的患者中，免疫触发因素是卵巢畸胎瘤和异位神经组织，并表达NMDAR。自那份报告以来，被诊断为这种疾病的患者数量迅速增加，类似的策略应用于其他神经精神症状患者，导致发现了4种针对细胞表面/突触自身抗原的新免疫反应，其中包括AMPA受体的GluR1/2亚单位和GABA(B1)受体。我们最近发表的研究表明，患者的NMDAR或AMPAR抗体减少了体外分离的海马神经元中受体簇的数量和突触定位，并且这些影响在从培养液中去除抗体后被逆转。这些发现导致了一种假设，即许多原因不明的急性脑病导致行为、个性和记忆障碍，可能是由影响细胞表面或突触位置的神经递质受体的抗体介导的。在初步研究显示脑脊液抗细胞表面/突触蛋白抗体的3种疾病中，包括快速进行性精神病；儿童的急性行为缺陷、语言障碍和缄默症；以及急性记忆缺陷和顺行性遗忘综合征，我们将执行2个目标：1)确定这3种疾病中自身抗原的身份，使用改良的高灵敏方法检测神经细胞表面/突触抗原抗体的存在；2)确定患者抗体如何在体外和体内改变啮齿动物神经元中突触的结构和功能，重点研究患者抗体如何改变抗原的密度和突触定位，以及抗体移除后这些恢复情况。这些实验的结果将使我们能够开始确定导致人类脑病及其相关行为表现的自身抗原的范围，并开始确定这些常见和毁灭性疾病的潜在分子、细胞和突触机制。我们建议对出现不明原因脑病的患者进行筛查，这些脑病导致自身免疫过程中的个性、行为和语言障碍。我们假设，患者抗体会影响神经细胞膜和突触上的神经递质受体，导致突触和回路功能的变化，进而导致行为、个性和记忆缺陷。拟议中的实验结果将为抗谷氨酸受体脑病潜在的分子、细胞、突触和行为机制提供新的见解，为这些疾病的特征记忆和认知缺陷提供新的见解，并可能为这些对公共健康产生重大影响的常见和破坏性记忆和认知障碍提供治疗干预的途径。 公共卫生相关性：我们建议对出现不明原因脑病的患者进行筛查，这些脑病导致自身免疫过程中的个性、行为和语言障碍。我们假设，患者抗体会影响神经细胞膜和突触上的神经递质受体，导致突触和回路功能的变化，进而导致行为、个性和记忆缺陷。拟议中的实验结果将为抗谷氨酸受体脑病潜在的分子、细胞、突触和行为机制提供新的见解，为这些疾病的特征记忆和认知缺陷提供新的见解，并可能为这些对公共健康产生重大影响的常见和破坏性记忆和认知障碍提供治疗干预的途径。