Department of Neurobiology, University of Alabama Birmingham, Birmingham, AL 35294-0021, USA.
Neuropsychopharmacology. 2012 Mar;37(4):896-905. doi: 10.1038/npp.2011.267. Epub 2011 Nov 2.
Recent evidence suggests that schizophrenia may result from alterations of integration of signaling mediated by multiple neurotransmitter systems. Abnormalities of associated intracellular signaling pathways may contribute to the pathophysiology of schizophrenia. Proteins and phospho-proteins comprising mitogen activated protein kinase (MAPK) and 3'-5'-cyclic adenosine monophosphate (cAMP)-associated signaling pathways may be abnormally expressed in the anterior cingulate (ACC) and dorsolateral prefrontal cortex (DLPFC) in schizophrenia. Using western blot analysis we examined proteins of the MAPK- and cAMP-associated pathways in these two brain regions. Postmortem samples were used from a well-characterized collection of elderly patients with schizophrenia (ACC=36, DLPFC=35) and a comparison (ACC=33, DLPFC=31) group. Near-infrared intensity of IR-dye labeled secondary antisera bound to targeted proteins of the MAPK- and cAMP-associated signaling pathways was measured using LiCor Odyssey imaging system. We found decreased expression of Rap2, JNK1, JNK2, PSD-95, and decreased phosphorylation of JNK1/2 at T183/Y185 and PSD-95 at S295 in the ACC in schizophrenia. In the DLPFC, we found increased expression of Rack1, Fyn, Cdk5, and increased phosphorylation of PSD-95 at S295 and NR2B at Y1336. MAPK- and cAMP-associated molecules constitute ubiquitous intracellular signaling pathways that integrate extracellular stimuli, modify receptor expression and function, and regulate cell survival and neuroplasticity. These data suggest abnormal activity of the MAPK- and cAMP-associated pathways in frontal cortical areas in schizophrenia. These alterations may underlie the hypothesized hypoglutamatergic function in this illness. Together with previous findings, these data suggest that abnormalities of intracellular signaling pathways may contribute to the pathophysiology of schizophrenia.
最近的证据表明，精神分裂症可能是由于多种神经递质系统介导的信号整合的改变所致。相关细胞内信号通路的异常可能导致精神分裂症的病理生理学。在前扣带回 (ACC) 和背外侧前额叶皮层 (DLPFC) 中，精神分裂症患者的丝裂原活化蛋白激酶 (MAPK) 和 3'-5'-环磷酸腺苷 (cAMP) 相关信号通路的蛋白和磷酸化蛋白可能异常表达。使用 Western blot 分析，我们检查了这两个脑区中 MAPK 和 cAMP 相关通路的蛋白。使用来自具有良好特征的老年精神分裂症患者尸检样本 (ACC=36，DLPFC=35) 和对照组 (ACC=33，DLPFC=31)。使用 LiCor Odyssey 成像系统测量针对 MAPK 和 cAMP 相关信号通路的靶向蛋白的近红外强度的 IR 染料标记二级抗血清。我们发现精神分裂症患者的 ACC 中 Rap2、JNK1、JNK2、PSD-95 的表达降低，JNK1/2 的 T183/Y185 和 PSD-95 的 S295 磷酸化降低。在 DLPFC 中，我们发现 Rack1、Fyn、Cdk5 的表达增加，PSD-95 的 S295 和 NR2B 的 Y1336 磷酸化增加。MAPK 和 cAMP 相关分子构成普遍存在的细胞内信号通路，可整合细胞外刺激、修饰受体表达和功能，并调节细胞存活和神经可塑性。这些数据表明，精神分裂症患者前额皮质区域的 MAPK 和 cAMP 相关途径异常活跃。这些改变可能是该疾病假设的谷氨酸能功能低下的基础。结合以前的发现，这些数据表明细胞内信号通路的异常可能导致精神分裂症的病理生理学。
