Schizophrenia is a chronic and disabling psychiatric disorder characterized by disturbances of thought, cognition, and behavior. Despite massive research efforts to date, the etiology and pathophysiology of schizophrenia remain largely unknown. The difficulty of brain research is largely a result of complex interactions between contributory factors at different scales: susceptible gene variants (molecular scale), synaptopathies (synaptic, dendritic, and cell scales), and alterations in neuronal circuits (circuit scale), which together result in behavioral manifestations (individual scale). It is likely that each scale affects the others, from the microscale to the mesoscale to the macroscale, and vice versa. Thus, to consider the intricate complexity of schizophrenia across multiple layers, we introduce a multi-scale, hierarchical view of the nature of this disorder, focusing especially on N-methyl-D-aspartate-type glutamate receptors (NMDARs). The reason for placing emphasis on NMDAR is its clinical relevance to schizophrenia, as well as its diverse functions in neurons, including the robust supralinear synaptic integration provided by N-methyl-D-aspartate-type glutamate (NMDA) spikes and the Ca²⁺ permeability of the NMDAR, which facilitates synaptic plasticity via various calcium-dependent proteins. Here, we review recent evidence implicating NMDARs in the pathophysiology of schizophrenia from the multi-scale perspective. We also discuss recent advances from optical techniques, which provide a powerful tool for uncovering the mechanisms of NMDAR synaptic pathology and their relationships, with subsequent behavioral manifestations.

中文翻译：

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对精神分裂症中NMDA受体功能的多尺度理解。

精神分裂症是一种慢性致残性精神病，其特征在于思想，认知和行为的紊乱。尽管迄今为止进行了大量的研究，但精神分裂症的病因学和病理生理学仍然未知。脑研究的困难很大程度上是由于不同尺度上的促成因素之间复杂的相互作用所致：易感基因变异（分子尺度），突触病（突触，树突和细胞尺度）以及神经元回路的改变（电路尺度）导致行为表现（个体量表）。从微观尺度到中尺度尺度到宏观尺度，每种尺度都有可能影响其他尺度，反之亦然。因此，考虑到跨多个层面的精神分裂症的复杂性，我们引入了多尺度，N-甲基-D-天冬氨酸型谷氨酸受体（NMDARs）。强调NMDAR的原因是其与精神分裂症的临床相关性以及其在神经元中的多种功能，包括由N-甲基-D-天冬氨酸型谷氨酸（NMDA）尖峰和Ca ²⁺提供的强大的超线性突触整合。NMDAR的通透性，通过各种钙依赖性蛋白促进突触可塑性。在这里，我们从多尺度角度回顾了有关NMDARs与精神分裂症的病理生理学相关的最新证据。我们还讨论了光学技术的最新进展，这些进展为揭示NMDAR突触病理学的机制及其相互关系以及随后的行为表现提供了强大的工具。