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

“重新审视 NMDA 受体功能减退：NMDA 受体消融小鼠模型中精神病的细胞机制”

• 批准号: 465418359
• 负责人: Professorin Dr. Sabine Liebscher
• 金额: --
• 依托单位: Klinik und Poliklinik für Neurologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/465418359?language=en
• 关键词: NMDA; receptor; hypofunction; revisited; Cellular

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.

遗传和免疫对NMDA受体（NMDAR）的干扰可以驱动类似精神病的内表型。然而，潜在的细胞和电路机制仍然知之甚少。为了确定导致精神病行为的电路中断的共同机制，我们在这里建议使用体内双光子成像方法来功能表征海马体内专用神经元群，这是一个对认知至关重要的区域，因此是精神病的阴性症状。基因消融的影响将在转基因小鼠模型中进行研究，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针对GluN1亚基的自身抗体来实现，这在人类中可引起一种称为抗nmdar受体自身免疫性脑炎（AE）的疾病。研究该疾病的新型小鼠模型将被开发并随后在体内进行测试。在确定受影响的电路元件后，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化学遗传学方法来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控制精神病中中断的信息处理的病理机制的理解，并确定新的治疗靶点，以选择性地修改专用大脑区域的电路功能。