Synaptic autoimmunity in neuropsychiatric diseases

近年来，抗神经元表面蛋白自身抗体引起的神经精神疾病越来越受到科学和临床的关注。典型的抗NMDA受体脑炎是一种相对常见的形式，具有特征性临床特征，包括精神症状、意识水平降低、癫痫发作和运动障碍。它是由针对NMDA受体的高度特异性自身抗体引起的。尽管预后良好，但大多数患者仍存在长期的注意力、计划和记忆缺陷。除了这些急性的，严重的记忆和行为的变化，在抗NMDA受体脑炎，相同的和相关的抗体，现在发现在孤立的症状，如精神分裂症样精神病和缓慢进行性认知能力下降类似原发性demential.There是令人信服的证据协会的数量减少的NMDA受体和几个神经精神疾病的病因。动物模型表明，出生后小鼠的NMDA受体的破坏甚至可以在很久以后导致明显类似于精神分裂症和NMDAR脑炎患者缺陷的症状。自己先前的数据显示，患者抗体以导致海马神经元细胞膜中这些和进一步突触受体可逆减少的方式结合NMDA受体。此外，免疫抑制治疗可显著改善患者的临床症状，同时降低抗体滴度，增加某些脑区的葡萄糖代谢。突触自身免疫的复杂分子病理机制无法在患者中探索，因此初步数据旨在建立合适的动物模型。在初步实验中，主动免疫的小鼠产生高血清滴度的NMDAR抗体。本文提出的研究项目应进一步验证这些动物的临床表型，并应回答以下问题：即使是小水平的致病性抗体如何导致临床症状，自身抗体的作用是否包括进一步的突触蛋白，哪些脑区在体内主要受影响，实验性免疫疗法是否会导致疾病相关自身抗体的长期丧失，以及短暂接触这些抗体是否会导致记忆和行为方面的神经精神异常延迟发生。这些问题的答案可能会揭示关于自身免疫与精神和记忆疾病之间因果关系的新的基础科学数据，特别是精神分裂症和痴呆症。以这种方式，本提案将阐明新的治疗尝试和疾病机制的一组神经精神疾病，目前没有具体的治疗选择。

Neuropsychiatric diseases resulting from auto-antibodies against neuronal surface proteins gained increasing scientific and clinical attention in recent years. The prototypical anti-NMDA receptor encephalitis is a relatively common form with characteristic clinical features including psychiatric symptoms, decreased levels of consciousness, epileptic seizures and dyskinesias. It is caused by highly specific autoantibodies directed against the NMDA receptor. Despite the favourable prognosis, most patients retain long-term deficits of attention, planning and memory. Besides these acute, severe changes of memory and behaviour in anti-NMDA receptor encephalitis, the same and related antibodies are now found in isolated symptoms such as schizophrenia-like psychosis and slowly progressive cognitive decline resembling primary dementia.There is compelling evidence for the association of a reduced number of NMDA receptors and the aetiology of several neuropsychiatric disorders. Animal models showed that disruption of NMDA receptors in postnatal mice could even much later result in symptoms that clearly resemble the deficits of patients with schizophrenia and NMDAR encephalitis. Own previous data showed that patient antibodies bind to NMDA receptors in a way that leads to reversible reduction of these and further synaptic receptors in the cell membrane of hippocampal neurons. In addition, immunosuppressive treatment in affected patients resulted in profound clinical improvement, parallel to reduction of antibody titers and increased glucose metabolism of certain brain areas.The complex molecular pathomechanisms of synaptic autoimmunity cannot be explored in patients, therefore preliminary data aimed at establishing a suitable animal model. In pilot experiments, actively immunized mice developed high serum titers of NMDAR antibodies. The here proposed research project should further validate the clinical phenotype of these animals and should answer the questions how even small levels of pathogenic antibodies result in clinical symptoms, whether the effect of autoantibodies includes further synaptic proteins, which brain areas are predominantly affected in vivo, whether experimental immunotherapies can lead to long-term loss of disease-related autoantibodies, and whether a transient exposure to these antibodies can result in delayed occurrence of neuropsychiatric abnormalities in memory and behaviour.Answers to these questions will likely reveal new fundamental scientific data about the causal relationship between autoimmunity and diseases of mind and memory, in particular schizophrenia and dementia. In this manner the present proposal will shed light on new therapeutic attempts and disease mechanisms for a group of neuropsychiatric disorders for which there is currently no specific therapeutic option.