Kristiansen L V, Beneyto M, Haroutunian V, Meador-Woodruff J H
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294-0017, USA.
Mol Psychiatry. 2006 Aug;11(8):737-47, 705. doi: 10.1038/sj.mp.4001844. Epub 2006 May 16.
Abnormal expression of the N-methyl-D-Aspartate (NMDA) receptor and its interacting molecules of the postsynaptic density (PSD) are thought to be involved in the pathophysiology of schizophrenia. Frontal regions of neocortex including dorsolateral prefrontal (DLPFC) and anterior cingulate cortex (ACC) are essential for cognitive and behavioral functions that are affected in schizophrenia. In this study, we have measured protein expression of two alternatively spliced isoforms of the NR1 subunit (NR1C2 and NR1C2') as well as expression of the NR2A-D subunits of the NMDA receptor in DLPFC and ACC in post-mortem samples from elderly schizophrenic patients and a comparison group. We found significantly increased expression of NR1C2' but not of NR1C2 in ACC, suggesting altered NMDA receptor cell membrane expression in this cortical area. We did not find significant changes in the expression of either of the NR1 isoforms in DLPFC. We did not detect changes of any of the NR2 subunits studied in either cortical area. In addition, we studied expression of the NMDA-interacting PSD molecules NF-L, SAP102, PSD-95 and PSD-93 in ACC and DLPFC at both transcriptional and translational levels. We found significant changes in the expression of NF-L in DLPFC, and PSD-95 and PSD-93 in ACC; increased transcript expression was associated with decreased protein expression, suggesting abnormal translation and/or accelerated protein degradation of these molecules in schizophrenia. Our findings suggest abnormal regional processing of the NMDA receptor and its associated PSD molecules, possibly involving transcription, translation, trafficking and protein stability in cortical areas in schizophrenia.
N-甲基-D-天冬氨酸（NMDA）受体及其突触后致密物（PSD）相互作用分子的异常表达被认为与精神分裂症的病理生理学有关。新皮质的额叶区域，包括背外侧前额叶（DLPFC）和前扣带回皮质（ACC），对于精神分裂症中受影响的认知和行为功能至关重要。在本研究中，我们测量了老年精神分裂症患者和对照组尸检样本中DLPFC和ACC中NR1亚基的两种选择性剪接异构体（NR1C2和NR1C2'）的蛋白表达以及NMDA受体NR2A-D亚基的表达。我们发现ACC中NR1C2'的表达显著增加，而NR1C2没有增加，这表明该皮质区域中NMDA受体细胞膜表达发生了改变。我们未发现DLPFC中任何一种NR1异构体的表达有显著变化。我们在两个皮质区域均未检测到所研究的任何NR2亚基的变化。此外，我们在转录和翻译水平上研究了ACC和DLPFC中与NMDA相互作用的PSD分子NF-L、SAP102、PSD-95和PSD-93的表达。我们发现DLPFC中NF-L的表达以及ACC中PSD-95和PSD-93的表达有显著变化；转录本表达增加与蛋白表达降低相关，这表明精神分裂症中这些分子存在异常翻译和/或蛋白降解加速。我们的研究结果表明，精神分裂症中NMDA受体及其相关PSD分子存在异常的区域加工，可能涉及皮质区域中的转录、翻译、运输和蛋白稳定性。
