Broadbelt Kevin, Jones Liesl B
Lehman College, CUNY, Department of Biological Sciences, 250 Bedford Park Blvd., Bronx, NY 10468, USA.
J Psychiatr Res. 2008 Jul;42(8):612-21. doi: 10.1016/j.jpsychires.2007.07.006. Epub 2008 Mar 4.
Schizophrenia is a severe neuropsychiatric disorder. Previous studies have implicated the prefrontal cortex (PFC) [Harrison PJ. The neuropathology of schizophrenia a critical review of the data and their interpretation. Brain 1999;122:593-624; Jones LB. Recent cytoarchitectonic changes in the prefrontal cortex of schizophrenics. Frontiers of Bioscience 2001;6:E148-53]. Recent immunocytochemical studies have shown a dramatic decrease in MAP2 and neurogranin [Jones L, Johnson N, Byne W. Alterations in MAP2 staining in area 9 and 32 of schizophrenic prefrontal cortex. Psychiatry Research 2002;114:137-48; Broadbelt K, Pamprasaud A, Jones LB. Evidence of altered neurogranin immunoreactivity in areas 9 and 32 of schizophrenic prefrontal cortex. Schizophrenia Research 2006;87:6-14] a loss of either is suggestive of dendritic lesions [Li GL, Farooque M, Lewen A., Lennmyr F, Holtz A., Olsson Y. MAP2 and neurogranin as markers for dendritic lesions in cns injury an immunohistochemical study in the rat. APMIS 2002;108:98-106.]. Neurogranin is an upstream regulator of calcium and calmodulin [Prichard L, Deloulmes JC, Storm DR. Interactions between Neurogranin and Calmodulin in vivo. Journal of Biological Chemistry 1999;274:7689-94]. A direct action of this pathway is the phosphorylation of MAP2, which is required for microtubule stabilization. Because of the above findings as well as moropholigical alterations [Broadbelt K, Byne W, Jones LB. Evidence for a decrease in primary and secondary basilar dendrites on pyramidal cells in area 32 of schizophrenic prefrontal cortex. Schizophrenia Research 2002;58:75-81] we examined the expression of the active form of calmodulin in layers III and V of areas 9 and 32 in six controls and six schizophrenics matched for age, sex, and postmortem interval. Using area fraction analysis we quantified immunostaining and counted the number of immunopositive pyramidal cells and interneurons as well as immunonegative pyramidal cells. Area fraction analysis showed a significant decrease in immunostaining in area nine layers III (58%) and V (44%), area 32 layers III (51%) and V (32%). We found a significant reduction in the density of immunopositive pyramidal cells in area 9 (11%) layer III, (20%) layer V, area 32 (16%) layer III and (17%) layer V with no difference in immunopositive interneurons. These data suggest a loss of the active form of calmodulin with pyramidal cells being preferentially affected suggesting that the calcium calmodulin dependent pathway may be altered in the pyramidal cells in the PFC.
精神分裂症是一种严重的神经精神障碍。先前的研究表明前额叶皮质（PFC）与之相关[哈里森·PJ。精神分裂症的神经病理学——对数据及其解释的批判性综述。《大脑》1999年；122:593 - 624；琼斯·LB。精神分裂症患者前额叶皮质近期的细胞结构变化。《生物科学前沿》2001年；6:E148 - 53]。近期的免疫细胞化学研究显示微管相关蛋白2（MAP2）和神经颗粒素显著减少[琼斯·L、约翰逊·N、拜恩·W。精神分裂症前额叶皮质9区和32区MAP2染色的改变。《精神病学研究》2002年；114:137 - 48；布罗德贝尔特·K、潘普拉萨德·A、琼斯·LB。精神分裂症前额叶皮质9区和32区神经颗粒素免疫反应性改变的证据。《精神分裂症研究》2006年；87:6 - 14]，其中任何一种的缺失都提示树突损伤[李·GL、法鲁克·M、勒文·A、伦米尔·F、霍尔茨·A、奥尔松·Y。MAP2和神经颗粒素作为中枢神经系统损伤中树突损伤的标志物——大鼠的免疫组织化学研究。《APMIS》2002年；108:98 - 106]。神经颗粒素是钙和钙调蛋白的上游调节因子[普里查德·L、德洛勒姆斯·JC、斯托姆·DR。体内神经颗粒素与钙调蛋白之间的相互作用。《生物化学杂志》1999年；274:7689 - 94]。该信号通路的直接作用是MAP2的磷酸化，这是微管稳定所必需的。基于上述发现以及形态学改变[布罗德贝尔特·K、拜恩·W、琼斯·LB。精神分裂症前额叶皮质32区锥体细胞初级和次级基底树突减少的证据。《精神分裂症研究》2002年；58:75 - 81]，我们检测了6名对照者和6名年龄、性别及死后间隔相匹配的精神分裂症患者9区和32区Ⅲ层和Ⅴ层中活性钙调蛋白的表达。使用面积分数分析，我们对免疫染色进行了定量，并计数了免疫阳性锥体细胞和中间神经元以及免疫阴性锥体细胞的数量。面积分数分析显示，9区Ⅲ层（58%）和Ⅴ层（%）、32区Ⅲ层（51%）和Ⅴ层（32%）的免疫染色显著减少。我们发现9区Ⅲ层（11%）、Ⅴ层（20%）、32区Ⅲ层（16%）和Ⅴ层（17%）中免疫阳性锥体细胞的密度显著降低，而免疫阳性中间神经元无差异。这些数据表明活性钙调蛋白缺失，锥体细胞受到优先影响，提示前额叶皮质锥体细胞中钙 - 钙调蛋白依赖性信号通路可能发生改变。
