“NMDA receptor hypofunction revisited: Cellular mechanisms of psychosis in mouse models of NMDA receptor ablation”

NMDA受体（NMDAR）的遗传和免疫干扰可以驱动内表型让人联想到精神病。然而，对潜在的细胞和电路机制仍然知之甚少。为了确定电路中断的常见机制，导致精神病行为，我们在这里提出使用体内双光子成像方法来功能性地表征海马内的专用神经元群体，海马是认知的重要区域，因此是精神病的阴性症状。将在转基因小鼠模型中研究基因消融的影响，其中NMDAR在兴奋性神经元或特定类型的中间神经元中被消融。免疫消融将通过应用靶向GluN1亚基的自身抗体来实现，GluN1亚基在人类中可引起称为抗NMDAR受体自身免疫性脑炎（AE）的疾病。将开发研究该疾病的新型小鼠模型，并随后进行体内测试。一旦识别出受影响的电路元件，例如特定的中间神经元细胞类型，我们将测试细胞类型选择性化学遗传方法，以恢复网络功能并最终挽救行为缺陷。通过这些实验，我们希望推进我们目前对精神病中信息处理中断的病理机制的理解，并确定新的治疗靶点，以选择性地改变专用脑区的回路功能。

Genetic and immunological interference with the NMDA receptor (NMDAR) can drive endophenotypes reminiscent of psychoses. The underlying cellular and circuit mechanisms, however, remain poorly understood. In order to identify common mechanisms of circuit disruption, leading to psychotic behavior, we here propose to use an in vivo two-photon imaging approach to functionally characterize dedicated neuronal populations within the hippocampus, a region vital for cognition and hence the negative symptoms of psychoses. The impact of genetic ablation will be investigated in transgenic mouse models, in which the NMDAR is ablated either in excitatory neurons or in a specific type of interneurons. Immunological ablation will be realized through the application of autoantibodies targeting the GluN1 subunit, which in humans can cause a disease called anti-NMDAR receptor autoimmune encephalitis (AE). Novel mouse models to study the disease will be developed and subsequently tested in vivo. Upon the identification of an affected circuit element, e.g. a particular interneuron cell type, we will test cell type selective chemogenetic approaches to restore network function and ultimately rescue behavioral deficits. With these experiments we hope to advance our current understanding of the pathomechanisms that govern disrupted information processing in psychoses and identify novel therapeutic targets to selectively modify circuit function in dedicated brain areas.