Perrone-Bizzozero N I, Sower A C, Bird E D, Benowitz L I, Ivins K J, Neve R L
Department of Biochemistry, University of New Mexico School of Medicine, Albuquerque 87131, USA.
Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):14182-7. doi: 10.1073/pnas.93.24.14182.
The pathophysiology of schizophrenia may involve perturbations of synaptic organization during development. The presence of cytoarchitectural abnormalities that may reflect such perturbations in the brains of patients with this disorder has been well-documented. Yet the mechanistic basis for these features of the disorder is still unknown. We hypothesized that altered regulation of the neuronal growth-associated protein GAP-43, a membrane phosphoprotein found at high levels in the developing brain, may play a role in the alterations in brain structure and function observed in schizophrenia. In the mature human brain, GAP-43 remains enriched primarily in association cortices and in the hippocampus, and it has been suggested that this protein marks circuits involved in the acquisition, processing, and/or storage of new information. Because these processes are known to be altered in schizophrenia, we proposed that GAP-43 levels might be altered in this disorder. Quantitative immunoblots revealed that the expression of GAP-43 is increased preferentially in the visual association and frontal cortices of schizophrenic patients, and that these changes are not present in other neuropsychiatric conditions requiring similar treatments. Examination of the levels of additional markers in the brain revealed that the levels of the synaptic vesicle protein synaptophysin are reduced in the same areas, but that the abundance of the astrocytic marker of neurodegeneration, the glial fibrillary acidic protein, is unchanged. In situ hybridization histochemistry was used to show that the laminar pattern of GAP-43 expression appears unaltered in schizophrenia. We propose that schizophrenia is associated with a perturbed organization of synaptic connections in distinct cortical associative areas of the human brain, and that increased levels of GAP-43 are one manifestation of this dysfunctional organization.
精神分裂症的病理生理学可能涉及发育过程中突触组织的紊乱。这种疾病患者大脑中存在可能反映此类紊乱的细胞结构异常，这一点已有充分记录。然而，该疾病这些特征的机制基础仍然未知。我们推测，神经元生长相关蛋白GAP - 43（一种在发育中的大脑中高表达的膜磷蛋白）调节的改变，可能在精神分裂症患者大脑结构和功能的改变中起作用。在成熟的人类大脑中，GAP - 43主要仍富集于联合皮质和海马体，并且有人提出这种蛋白质标记参与新信息获取、处理和/或存储的神经回路。因为已知这些过程在精神分裂症中会发生改变，所以我们提出GAP - 43水平在这种疾病中可能会发生改变。定量免疫印迹显示，精神分裂症患者的GAP - 43表达在视觉联合皮质和额叶皮质中优先增加，并且在需要类似治疗的其他神经精神疾病中不存在这些变化。对大脑中其他标志物水平的检测显示，突触囊泡蛋白突触素在相同区域的水平降低，但神经退行性变的星形胶质细胞标志物胶质纤维酸性蛋白的丰度未变。原位杂交组织化学用于显示GAP - 43表达的分层模式在精神分裂症中似乎未改变。我们提出，精神分裂症与人脑不同皮质联合区域突触连接的紊乱有关，并且GAP - 43水平升高是这种功能失调组织的一种表现。
