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）拮抗剂的拟精神作用和抗NMDAR脑炎患者所经历的精神病症状支持NMDA介导的谷氨酸能功能障碍在引发精神病中的因果作用。然而，全局NMDAR功能障碍诱导许多其他（特别是神经系统）症状，而只有特定的、未知的神经元群可能与精神病有关。我们的目标是通过药物遗传学方法在小鼠中确定哪些神经元群与诱导青春期晚期nmdar介导的精神病有关。为此，我们将生成3个时间和细胞限制性他莫昔芬诱导的NMDAR消融小鼠系。在第一行中，NMDAR将在新皮质/海马小白蛋白（PV）阳性的gaba能中间神经元中被删除，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。第二组实验用诱导NMDAR消融腹侧被盖区（VTA）多巴胺神经元的小鼠，可能涉及与精神病相关的多巴胺失调。在第三个系列中，NMDAR将在表达erbB4的神经元中消融，erbB4是精神分裂症危险因子神经调节蛋白1的受体。表达erbb4的神经元代表了更大的群体，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受体表达的Calleja岛。所有这些神经元群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。分析将包括多种行为，神经化学和电生理分析。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。最终目标是澄清精神病和相关异常中特定神经元群的贡献，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.