Parkin Georgia M, Gibbons Andrew, Udawela Madhara, Dean Brian
The Molecular Psychiatry Laboratory, The Florey Institute for Neuroscience and Mental Health, Parkville, Victoria, Australia; The Cooperative Research Centre for Mental Health, Parkville, Victoria, Australia.
The Molecular Psychiatry Laboratory, The Florey Institute for Neuroscience and Mental Health, Parkville, Victoria, Australia.
J Psychiatr Res. 2020 Apr;123:151-158. doi: 10.1016/j.jpsychires.2020.02.004. Epub 2020 Feb 8.
Excitatory amino acid transporter (EAAT)1 and EAAT2 mediate glutamatergic neurotransmission and prevent excitotoxicity through binding and transportation of glutamate into glia. These EAATs may be regulated by metabotropic glutamate receptor 5 (mGluR5), which is also expressed by glia. Whilst we have data from an Affymetrix™ Human Exon 1.0 ST Array showing higher levels of EAAT1 mRNA (+36%) in Brodmann's are (BA)9 of subjects with schizophrenia, there is evidence that EAAT1 and EAAT2, as well as mGluR5 levels, are altered in the cortex of subjects with the disorder. Hence, we measured mRNA levels of these genes in other cortical regions in subjects with that disorder. EAAT1, EAAT2 and mGluR5 mRNA were measured, in triplicate, using Quantitative PCR in BA10 and BA46 from subjects with schizophrenia (n = 20) and age and sex matched controls (n = 18). Levels of mRNA were normalised to the geometric mean of two reference genes, transcription factor B1, mitochondrial (TFB1M) and S-phase kinase-associated protein 1A (SKP1A), for which mRNA did not vary between diagnostic groups in either region. Normalised levels of EAAT1 and EAAT2 mRNA were significantly higher in BA10 (EAAT1: U = 58, p = 0.0002; EAAT2 U = 70, p = 0.0009), but not BA46 (EAAT1: U = 122, p = 0.09; EAAT2: U = 136, p = 0.21), from subjects with schizophrenia compared to controls. mGluR5 levels in BA10 (U = 173, p=0.85) and BA46 (U = 178, p = 0.96) did not vary by cohort. Our data suggests that region-specific increases in cortical EAAT1 and EAAT2 mRNA are involved in schizophrenia pathophysiology and that disrupted glutamate uptake in schizophrenia may be of particular significance in BA10.
兴奋性氨基酸转运体（EAAT）1和EAAT2介导谷氨酸能神经传递，并通过将谷氨酸结合并转运到神经胶质细胞中来预防兴奋性毒性。这些EAAT可能受代谢型谷氨酸受体5（mGluR5）调节，神经胶质细胞也表达mGluR5。虽然我们有来自Affymetrix™人类外显子1.0 ST阵列的数据显示，精神分裂症患者布罗德曼区（BA）9中EAAT1 mRNA水平更高（+36%），但有证据表明，EAAT1和EAAT2以及mGluR5水平在该疾病患者的皮质中发生了改变。因此，我们测量了该疾病患者其他皮质区域中这些基因的mRNA水平。使用定量PCR对精神分裂症患者（n = 20）以及年龄和性别匹配的对照组（n = 18）的BA10和BA46中的EAAT1、EAAT2和mGluR5 mRNA进行了三次测量。将mRNA水平标准化为两个参考基因（线粒体转录因子B1（TFB1M）和S期激酶相关蛋白1A（SKP1A））的几何平均值，这两个参考基因的mRNA在任一区域的诊断组之间均无差异。与对照组相比，精神分裂症患者BA10中EAAT1和EAAT2 mRNA的标准化水平显著更高（EAAT1：U = 58，p = 0.0002；EAAT2：U = 70，p = 0.0009），但BA46中并非如此（EAAT1：U = 122，p = 0.09；EAAT2：U = 136，p = 0.21）。BA10（U = 173，p = 0.85）和BA46（U = 178，p = 0.96）中的mGluR5水平在不同队列中没有变化。我们的数据表明，皮质EAAT1和EAAT2 mRNA的区域特异性增加与精神分裂症的病理生理学有关，并且精神分裂症中谷氨酸摄取的破坏在BA10中可能具有特别重要的意义。
