Synaptic autoimmunity in neuropsychiatric diseases

近年来，由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，但大多数患者仍存在长期的注意力、计划和记忆缺陷。除了抗nmda受体脑炎的这些急性、严重的记忆和行为改变外，现在在孤立的症状，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衰退中也发现了相同的相关抗体。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NMDA受体的破坏甚至可能在很久以后导致明显类似精神分裂症和NMDA脑炎患者缺陷的症状。先前的数据表明，患者抗体与NMDA受体结合的方式导致海马神经元细胞膜中这些和进一步的突触受体的可逆减少。此外，在受影响的患者中，免疫抑制治疗导致了深刻的临床改善，平行于抗体滴度的降低和某些脑区域葡萄糖代谢的增加。突触自身免疫在患者体内复杂的分子病理机制尚不清楚，因此初步数据旨在建立合适的动物模型。在中试实验中，主动免疫小鼠产生了高血清滴度的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，体内主要影响哪些脑区，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上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，特别是精神分裂症和痴呆症之间因果关系的新的基础科学数据。以这种方式，本提案将阐明一组目前没有特定治疗选择的神经精神疾病的新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.