Schizophrenia, a debilitating psychiatric disorder, displays considerable interindividual variation in clinical presentations. The ongoing debate revolves around whether this heterogeneity signifies a continuum of severity linked to a singular causative factor or a collection of distinct subtypes with unique origins. Within the realm of schizophrenia, the functional impairment of GluN2A, a subtype of the NMDA receptor, has been associated with an elevated risk. Despite GluN2A’s expression across various neuronal types throughout the brain, its specific contributions to schizophrenia and its involvement in particular cell types or brain regions remain unexplored. We generated age-specific, cell type-specific or brain region-specific conditional knockout mice targeting GluN2A and conducted a comprehensive analysis using tests measuring phenotypes relevant to schizophrenia. Through the induction of germline ablation of GluN2A, we observed the emergence of numerous schizophrenia-associated abnormalities in adult mice. Intriguingly, GluN2A knockout performed at different ages, in specific cell types and within distinct brain regions, we observed overlapping yet distinct schizophrenia-related phenotypes in mice. Our interpretation suggests that the dysfunction of GluN2A is sufficient to evoke heterogeneous manifestations associated with schizophrenia, indicating that GluN2A stands as a prominent risk factor and a potential therapeutic target for schizophrenia. This project received support from the (Grant No. ) awarded to Y.C. and the (Grant No. and ) awarded to G.Y.

中文翻译：

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GluN2A 的差异性消耗会诱导小鼠出现异质性精神分裂症相关表型

精神分裂症是一种使人衰弱的精神疾病，其临床表现存在相当大的个体差异。持续的争论围绕着这种异质性是否意味着与单一致病因素相关的严重程度的连续性，或与具有独特起源的不同亚型的集合有关。在精神分裂症领域，GluN2A（NMDA 受体的一种亚型）的功能障碍与风险升高相关。尽管 GluN2A 在整个大脑的各种神经元类型中表达，但它对精神分裂症的具体贡献以及它在特定细胞类型或大脑区域中的参与仍未被探索。我们生成了针对 GluN2A 的年龄特异性、细胞类型特异性或大脑区域特异性条件敲除小鼠，并使用测量与精神分裂症相关表型的测试进行了全面分析。通过诱导 GluN2A 种系消融，我们观察到成年小鼠出现了许多与精神分裂症相关的异常。有趣的是，在不同年龄、特定细胞类型和不同大脑区域内进行 GluN2A 敲除，我们在小鼠中观察到重叠但不同的精神分裂症相关表型。我们的解释表明，GluN2A 的功能障碍足以引起与精神分裂症相关的异质表现，表明 GluN2A 是精神分裂症的一个突出的危险因素和潜在的治疗靶点。该项目得到了YC的（拨款号）和GY的（拨款号和）的支持