The role of abnormal NMDA receptor-mediated transmission in specific neuronal populations in the post-adolescent onset of psychosis

大量证据，包括NMDA受体（NMDAR）拮抗剂的拟精神病效应和患有抗NMDAR脑炎的患者所经历的精神病症状，支持NMDAR介导的神经元功能障碍在触发精神病中的因果作用。然而，整体NMDAR功能障碍诱导许多其他（特别是神经）症状，而只有特定的，但未知的神经元群体可能涉及精神病。我们的目的是确定在这里通过药物遗传学的方法在小鼠中的神经元群体参与诱导NMDAR介导的精神病在青春期后期。为此，我们将产生3个小鼠系，其具有NMDAR的时间和细胞限制性他莫昔芬诱导消融。在第一行中，NMDAR将在新皮层/海马小清蛋白（PV）阳性GABA能中间神经元中缺失，这在产生振荡活动和伴随精神病的异常神经元同步中至关重要。第二条线由在腹侧被盖区（VTA）多巴胺神经元中具有诱导型NMDAR消融的小鼠代表，可能涉及与精神病相关的多巴胺失调。在第三线中，NMDAR将在表达erbB 4的神经元中被消融，erbB 4是精神分裂症风险因子神经调节蛋白1的受体。erbB 4表达神经元代表了一个更大的群体，包括PV阳性中间神经元和VTA多巴胺神经元，以及纹状体多巴胺水平的其他重要调节剂，多巴胺D3受体表达Calleja岛。所有这些神经元群体通过调节振荡活动和多巴胺功能的多个功能回路相互连接。该分析将包括多种行为、神经化学和电生理测定。它将侧重于分析与精神病相关的行为/认知功能，同步性和多巴胺能失调的变化。最终的目标是阐明特定神经元群体在精神病和相关异常中的作用，以开发有效的早期治疗干预措施。

A vast body of evidence including the psychotomimetic effect of NMDA receptor (NMDAR) antagonists and the psychotic symptoms experienced by patients suffering from anti-NMDAR encephalitis support a causal role of NMDAR-mediated glutamatergic dysfunction in triggering psychosis. However, global NMDAR dysfunction induces numerous other (especially neurological) symptoms, whereas only specific, yet unknown neuronal populations may be implicated in psychosis. We aim to identify here by a pharmacogenetic approach in mice which neuronal populations are implicated in inducing NMDAR-mediated psychosis during late adolescence. For this purpose, we will generate 3 mouse lines with time- and cell-restricted tamoxifen-inducible ablation of NMDAR. In the first line, NMDAR will be deleted in neocortical/hippocampal parvalbumin (PV)-positive GABAergic interneurons, critical in generating oscillatory activity and in aberrant neuronal synchronization accompanying psychosis. A second line is represented by mice with inducible NMDAR ablation in ventral tegmental area (VTA) dopamine neurons, possibly implicated in dopamine dysregulation associated with psychosis. In a third line NMDAR will be ablated in neurons expressing erbB4, the receptor for the schizophrenia risk factor neuregulin 1. The erbB4-expressing neurons represent a larger population that comprises both PV-positive interneurons and VTA dopamine neurons, as well as other important modulators of striatal dopamine levels, the dopamine D3 receptor-expressing Islands of Calleja. All these neuronal populations are interconnected by multiple functional loops regulating oscillatory activity and dopamine function. The analysis will comprise multiple behavioural, neurochemical and electrophysiological assays. It will focus on analysis of changes in behaviour/cognitive function, synchronicity and dopaminergic dysregulation associated with psychosis. The final goal is to clarify the contribution of specific neuronal populations in psychosis and associated abnormalities, towards developing effective early therapeutic interventions.