Nakazawa Kazu, Jeevakumar Vivek, Nakao Kazuhito
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL USA.
NPJ Schizophr. 2017 Feb 3;3:7. doi: 10.1038/s41537-016-0003-3. eCollection 2017.
The -methyl-d-aspartate receptor hypofunction is one of the most prevalent models of schizophrenia. For example, healthy subjects treated with uncompetitive -methyl-d-aspartate receptor antagonists elicit positive, negative, and cognitive-like symptoms of schizophrenia. Patients with anti--methyl-d-aspartate receptor encephalitis, which is likely caused by autoantibody-mediated down-regulation of cell surface -methyl-d-aspartate receptors, often experience psychiatric symptoms similar to schizophrenia initially. However, where and when -methyl-d-aspartate receptor hypofunction occurs in the brain of schizophrenic patients is poorly understood. Here we review the findings from -methyl-d-aspartate receptor antagonist and autoantibody models, postmortem studies on -methyl-d-aspartate receptor subunits, as well as the global and cell-type-specific knockout mouse models of subunit GluN1. We compare various conditional GluN1 knockout mouse strains, focusing on the onset of -methyl-d-aspartate receptor deletion and on the cortical cell-types. Based on these results, we hypothesize that -methyl-d-aspartate receptor hypofunction initially occurs in cortical GABAergic neurons during early postnatal development. The resulting GABA neuron maturation deficit may cause reduction of intrinsic excitability and GABA release, leading to disinhibition of pyramidal neurons. The cortical disinhibition in turn could elicit glutamate spillover and subsequent homeostatic down regulation of -methyl-d-aspartate receptor function in pyramidal neurons in prodromal stage. These two temporally-distinct -methyl-d-aspartate receptor hypofunctions may be complimentary, as neither alone may not be able to fully explain the entire schizophrenia pathophysiology. Potential underlying mechanisms for -methyl-d-aspartate receptor hypofunction in cortical GABA neurons are also discussed, based on studies of naturally-occurring -methyl-d-aspartate receptor antagonists, neuregulin/ErbB4 signaling pathway, and theoretical analysis of excitatory/inhibitory balance.
N-甲基-D-天冬氨酸受体功能减退是精神分裂症最常见的模型之一。例如，用非竞争性N-甲基-D-天冬氨酸受体拮抗剂治疗的健康受试者会出现精神分裂症的阳性、阴性和认知样症状。抗N-甲基-D-天冬氨酸受体脑炎患者，可能是由自身抗体介导的细胞表面N-甲基-D-天冬氨酸受体下调所致，最初常出现类似于精神分裂症的精神症状。然而，精神分裂症患者大脑中N-甲基-D-天冬氨酸受体功能减退发生的部位和时间尚不清楚。在此，我们综述了N-甲基-D-天冬氨酸受体拮抗剂和自身抗体模型、N-甲基-D-天冬氨酸受体亚基的死后研究以及亚基GluN1的整体和细胞类型特异性敲除小鼠模型的研究结果。我们比较了各种条件性GluN1敲除小鼠品系，重点关注N-甲基-D-天冬氨酸受体缺失的起始阶段和皮质细胞类型。基于这些结果，我们推测N-甲基-D-天冬氨酸受体功能减退最初发生在出生后早期发育阶段的皮质GABA能神经元中。由此导致的GABA神经元成熟缺陷可能会导致内在兴奋性和GABA释放减少，从而导致锥体神经元去抑制。皮质去抑制进而可能引发谷氨酸溢出，并随后在前驱期锥体神经元中对N-甲基-D-天冬氨酸受体功能进行稳态下调。这两种在时间上不同的N-甲基-D-天冬氨酸受体功能减退可能是互补的，因为单独一种可能无法完全解释整个精神分裂症的病理生理学。基于对天然存在的N-甲基-D-天冬氨酸受体拮抗剂、神经调节蛋白/ErbB4信号通路的研究以及兴奋性/抑制性平衡的理论分析，我们还讨论了皮质GABA神经元中N-甲基-D-天冬氨酸受体功能减退的潜在潜在机制。
