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，具有典型的临床特征，包括精神症状、意识水平下降、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，但大多数患者仍长期缺乏注意力、计划和记忆。除了抗NMDA受体脑炎患者记忆和行为的这些急性、严重变化外，现在在一些孤立的症状中也发现了相同和相关的抗体，如精神分裂症样精神病和类似原发性痴呆的缓慢进行性认知能力下降。有令人信服的证据表明，NMDA受体数量的减少与几种神经精神疾病的病因有关。动物模型显示，出生后小鼠的NMDA受体中断甚至可能在很长一段时间后导致明显类似于精神分裂症和NMDAR脑炎患者的症状。自己之前的数据显示，患者抗体与NMDA受体结合的方式导致海马神经元细胞膜上这些受体和进一步的突触受体可逆性减少。此外，免疫抑制治疗能显著改善患者的临床症状，同时降低抗体效价，增加某些脑区的糖代谢。目前尚不能探讨患者突触自身免疫的复杂分子病理机制，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了高滴度的NMDAR抗体。这里提出的研究项目应该进一步验证这些动物的临床表型，并回答以下问题：即使是少量的致病抗体也会导致临床症状；自身抗体的影响是否包括更多的突触蛋白；体内哪些大脑区域主要受到影响；实验性免疫疗法是否会导致与疾病相关的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的神经精神异常延迟发生。回答这些问题可能会揭示关于自身免疫与精神和记忆疾病，特别是精神分裂症和痴呆症之间因果关系的新的基本科学数据。通过这种方式，本提案将阐明目前没有具体治疗选择的一组神经精神障碍的新的治疗尝试和疾病机制。

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.