Ghose Subroto, Chin Ronald, Gallegos Analysa, Roberts Rosalinda, Coyle Joseph, Tamminga Carol
University of Texas Southwestern Medical Center, Dallas, TX 75390-9127, USA.
Schizophr Res. 2009 Jun;111(1-3):131-7. doi: 10.1016/j.schres.2009.03.038. Epub 2009 Apr 28.
N-acetyl aspartyl glutamate (NAAG) is an endogenous agonist at the metabotropic glutamate receptor 3 (mGluR3,GRM3) receptor and antagonist at the N-methyl d-aspartate (NMDA) receptor, both receptors important to the pathophysiology of schizophrenia. Glutamate carboxypeptidase II (GCPII), an enzyme that metabolizes NAAG, is also implicated in this illness. In this study, we conducted in situ hybridization experiments to examine expression of mGluR3 and GCPII transcripts along the rostrocaudal axis of the human postmortem hippocampus. We hypothesized that we would find changes in mGluR3 and/or GCPII in the AH but not posterior hippocampus (PH) in schizophrenia. We compared mRNA levels of these genes in the dentate gyrus (DG) and cornu ammonis (CA)1 and CA3 of AH and PH in 20 matched pairs of control and schizophrenia cases. In controls, mGluR3 is highly expressed in the DG and at lower levels in CA1 and CA3 while GCP II is expressed at similar levels in these regions. Group comparisons show a significant reduction of GCPII mRNA level in the AH in schizophrenia. Post hoc analyses reveal this difference is localized to the CA1 region. In addition, we find a significant positive correlation between GCPII and mGluR3 mRNA in the CA3 of the control AH (r=0.66, p=0.008) which is not present in schizophrenia (r=0.096, p=0.76). This may reflect a disrupted functional interaction between NAAG and mGluR3 in CA3 in schizophrenia. These data suggest that NAAG-mediated signaling is disrupted in the AH in schizophrenia and localize the defect to the CA1 and CA3 regions.
N-乙酰天门冬氨酰谷氨酸（NAAG）是代谢型谷氨酸受体3（mGluR3，GRM3）的内源性激动剂，也是N-甲基-D-天冬氨酸（NMDA）受体的拮抗剂，这两种受体对精神分裂症的病理生理学都很重要。谷氨酸羧肽酶II（GCPII）是一种代谢NAAG的酶，也与这种疾病有关。在本研究中，我们进行了原位杂交实验，以检查人死后海马体前后轴上mGluR3和GCPII转录本的表达。我们假设，在精神分裂症患者中，我们会在杏仁核（AH）而非后海马体（PH）中发现mGluR3和/或GCPII的变化。我们比较了20对匹配的对照和精神分裂症病例的AH和PH的齿状回（DG）、海马角（CA）1和CA3中这些基因的mRNA水平。在对照组中，mGluR3在DG中高表达，在CA1和CA3中表达水平较低，而GCP II在这些区域的表达水平相似。组间比较显示，精神分裂症患者AH中的GCPII mRNA水平显著降低。事后分析表明，这种差异局限于CA1区域。此外，我们发现对照AH的CA3中GCPII和mGluR3 mRNA之间存在显著正相关（r=0.66，p=0.008），而在精神分裂症患者中不存在这种相关性（r=0.096，p=0.76）。这可能反映了精神分裂症患者CA3中NAAG和mGluR3之间的功能相互作用被破坏。这些数据表明，精神分裂症患者的AH中NAAG介导的信号传导被破坏，并且缺陷定位于CA1和CA3区域。
