Department of Psychiatry, Hokkaido University Graduate School of Medicine, West 7, North 15, Kita Ward, Sapporo City, Hokkaido 060-8638, JAPAN.
Department of Psychiatry, Hokkaido University Graduate School of Medicine, West 7, North 15, Kita Ward, Sapporo City, Hokkaido 060-8638, JAPAN.
Prog Neuropsychopharmacol Biol Psychiatry. 2020 Dec 20;103:109984. doi: 10.1016/j.pnpbp.2020.109984. Epub 2020 May 28.
The dopamine and glutamate hypotheses reflect only some of the pathophysiological changes associated with schizophrenia. We have proposed a new "comprehensive progressive pathophysiology model" based on the "dopamine to glutamate hypothesis." Repeated administration of methamphetamine (METH) at a dose of 2.5 mg/kg in rats has been used to assess dynamic changes in the pathophysiology of schizophrenia. Previous use of this model suggested N-methyl-d-aspartate receptor (NMDA-R) dysfunction, but the mechanism could only be inferred from limited, indirect observations. In the present study, we used this model to investigate changes in the expression of NMDA-R subunits. Repeated administration of METH significantly decreased the gene expression levels of glutamate ionotropic receptor NMDA type subunit (Grin) subtypes Grin1 and Grin2c in the prefrontal cortex (PFC), Grin1 and Grin2a in the hippocampus (HPC), and Grin1, Grin2b, and Grin2d in the striatum (ST).We observed a significant difference in Grin1 expression between the PFC and ST. Furthermore, repeated administration of METH significantly decreased the protein expression of GluN1 in both cytosolic and synaptosomal fractions isolated from the PFC, and significantly decreased the protein expression of GluN1 in the cytosolic fraction, but not the synaptosomal fraction from the ST. These regional differences may be due to variations in the synthesis of GluN1 or intracellular trafficking events in each area of the brain. Considering that knockdown of Grin1 in mice affects vulnerability to develop schizophrenia, these results suggest that this model reflects some of the pathophysiological changes of schizophrenia, combining both the dopamine and glutamate hypotheses.
多巴胺和谷氨酸假说仅反映了与精神分裂症相关的部分病理生理变化。我们基于“多巴胺到谷氨酸假说”提出了一个新的“全面进行性病理生理学模型”。在大鼠中，以 2.5mg/kg 的剂量重复给予甲基苯丙胺（METH）已被用于评估精神分裂症病理生理学的动态变化。此前使用该模型表明 N-甲基-D-天冬氨酸受体（NMDA-R）功能障碍，但该机制只能从有限的、间接的观察中推断出来。在本研究中，我们使用该模型研究了 NMDA-R 亚基表达的变化。METH 的重复给药显著降低了前额叶皮层（PFC）中谷氨酸离子型受体 NMDA 型亚基（Grin）亚型 Grin1 和 Grin2c、海马（HPC）中 Grin1 和 Grin2a 以及纹状体（ST）中 Grin1、Grin2b 和 Grin2d 的基因表达水平。我们观察到 PFC 和 ST 中 Grin1 表达的显著差异。此外，METH 的重复给药显著降低了从 PFC 分离的细胞质和突触小体部分中 GluN1 的蛋白表达，并且显著降低了细胞质部分中的 GluN1 蛋白表达，但不降低 ST 中的突触小体部分中的 GluN1 蛋白表达。这些区域差异可能是由于每个脑区的 GluN1 合成或细胞内转运事件的变化所致。考虑到在小鼠中敲低 Grin1 会影响发展为精神分裂症的易感性，这些结果表明该模型反映了一些精神分裂症的病理生理变化，结合了多巴胺和谷氨酸假说。
