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

描述（由申请人提供）：本申请涉及广泛的挑战领域（01）：行为，行为改变和预防，以及特定的挑战主题01- aa -102：神经免疫因子在调节行为中的功能作用。本提案的重点是表征自身免疫反应突触蛋白，导致行为，记忆，认知和精神病的障碍。2007年，我们首次报道了一组急性发展为精神病性行为或精神分裂症的年轻女性，随后出现记忆减退、紧张症、异常运动和自主神经功能障碍。利用我们优化的检测神经元细胞表面和/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亚基的抗体，NMDA受体是一种谷氨酸受体，在突触传递和可塑性中起重要作用。在大约60%的患者中，免疫触发是卵巢畸胎瘤与异位的神经组织和表达NMDAR。自那篇报道以来，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表现的患者，导致发现了4种针对细胞表面/突触自身抗原的新型免疫反应，其中包括AMPA受体的GluR1/2亚基和GABA（B1）受体。我们最近发表的研究表明，在体外，患者的NMDAR或AMPAR抗体减少了游离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，这些作用被逆转。这些发现导致了一种假设，即许多病因不明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的神经递质受体的抗体介导的。初步研究显示脑脊液对细胞表面/突触蛋白有抗体的3种疾病，包括快速进行性精神病；儿童的急性行为缺陷、语言障碍和缄默症和急性记忆缺陷和顺行性遗忘综合征，我们将实现两个目标：1)确定这3种疾病的自身抗原的身份，使用改进的高灵敏度方法检测神经元细胞表面/突触抗原抗体的存在；2)确定患者抗体在体外和体内如何改变啮齿动物神经元突触的结构和功能，重点关注患者抗体如何改变抗原的密度和突触定位，以及抗体去除后这些结构和功能如何恢复。这些实验的结果将使我们能够开始确定导致人类脑病与相关行为表现的自身抗原的范围，并开始确定这些常见和破坏性疾病的潜在分子，细胞和突触机制。我们建议筛查患有不明病因脑病的患者，这些脑病会导致自身免疫过程中的人格、行为和语言功能障碍。我们假设患者抗体影响神经元膜和突触中的神经递质受体，导致突触和电路功能的改变，进而导致行为、人格和记忆缺陷。这些实验的结果将从根本上为抗谷氨酸受体脑病的分子、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，并可能为这些具有重大公共卫生影响的常见和破坏性记忆和认知障碍的治疗干预提供途径。

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.