Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
Schizophr Res. 2022 Nov;249:63-73. doi: 10.1016/j.schres.2020.10.004. Epub 2020 Nov 11.
Numerous genetic and postmortem studies link N-methyl-d-aspartate receptor (NMDAR) dysfunction with schizophrenia, forming the basis of the popular glutamate hypothesis. Neuronal NMDAR abnormalities are consistently reported from both basic and clinical experiments, however, non-neuronal cells also contain NMDARs, and are rarely, if ever, considered in the discussion of glutamate action in schizophrenia. We offer an examination of recent discoveries elucidating the actions and consequences of NMDAR activation in the neuroendothelium. While there has been mixed literature regarding blood flow alterations in the schizophrenia brain, in this review, we posit that some common findings may be explained by neuroendothelial NMDAR dysfunction. In particular, we emphasize that endothelial NMDARs are key mediators of neurovascular coupling, where increased neuronal activity leads to increased blood flow. Based on the broad conclusions that hypoperfusion is a neuroanatomical finding in schizophrenia, we discuss potential mechanisms by which endothelial NMDARs contribute to this disorder. We propose that endothelial NMDAR dysfunction can be a primary cause of neurovascular abnormalities in schizophrenia. Importantly, functional MRI studies using BOLD signal as a proxy for neuron activity should be considered in a new light if neurovascular coupling is impaired in schizophrenia. This review is the first to propose that NMDARs in non-excitable cells play a role in schizophrenia.
大量的遗传学和尸检研究将 N-甲基-D-天冬氨酸受体 (NMDAR) 功能障碍与精神分裂症联系起来，这构成了谷氨酸假说的基础。基础和临床实验都一致报道了神经元 NMDAR 的异常，但很少（如果有的话）将非神经元细胞纳入精神分裂症中谷氨酸作用的讨论中。我们提供了对最近发现的检查，这些发现阐明了神经内皮细胞中 NMDAR 激活的作用和后果。尽管关于精神分裂症大脑中血流改变的文献存在分歧，但在本综述中，我们假设一些常见的发现可以通过神经内皮细胞 NMDAR 功能障碍来解释。特别是，我们强调内皮细胞 NMDAR 是神经血管耦联的关键介质，其中神经元活动增加会导致血流量增加。基于灌注不足是精神分裂症中的神经解剖学发现这一广泛结论，我们讨论了内皮细胞 NMDAR 如何导致这种疾病的潜在机制。我们提出，内皮细胞 NMDAR 功能障碍可能是精神分裂症中神经血管异常的主要原因。重要的是，如果精神分裂症中的神经血管耦联受损，那么使用 BOLD 信号作为神经元活动的替代物的功能磁共振成像研究应该被重新考虑。这是第一篇提出非兴奋性细胞中的 NMDAR 在精神分裂症中起作用的综述。
