Blennow K, Bogdanovic N, Gottfries C G, Davidsson P
Göteborg University, Institute of Clinical Neuroscience, Department of Psychiatry and Neurochemistry, Sahlgren's University Hospital, Mölndal, Sweden.
J Mol Neurosci. 1999 Aug-Oct;13(1-2):101-9. doi: 10.1385/JMN:13:1-2:101.
Schizophrenia is a common and severe psychiatric disorder of unknown etiology. Numerous neuropathological studies have found subtle structural changes in limbic structures, especially medial temporal lobe structures and the gyrus cinguli. To test the hypothesis that synaptic disturbances are involved in the pathogenesis of schizophrenia, we studied the growth-associated protein 43 (GAP-43), a protein localized to presynaptic terminals, suggested to be involved in establishment and remodeling of synaptic connections, in postmortem brain tissue, using quantitative Western blotting immunohistochemistry. The material consisted of brain tissue from 17 schizophrenics (80 +/- 11 yr), diagnosed according to the DSM-III-R criteria, and 20 age-matched controls (75 +/- 13 yr). Quantitative analyses showed increased GAP-43 protein levels in schizophrenic compared to control brains, both in the hippocampus (2.43 +/- 0.78 vs 1.00 +/- 0.29; p < 0.0001) and in the gyrus cinguli (1.52 +/- 0.21 vs 1.00 +/- 0.35; p < 0.0001). Also by immunohistochemistry, increased GAP-43 staining was found in schizophrenic compared with control brains, throughout all layers of the gyrus cinguli and the hippocampus. Anomalous synaptic sprouting and reorganization, with resultant "miswiring," as well as a defect in synaptic pruning have been hypothesized to be pathogenetic factors in schizophrenia. We suggest that a decreased synaptic density, whether caused by disturbed development or damage/degeneration, may elicit a reactive synaptogenesis (reflected by an increase in GAP-43), which may be functional or anomalous. Synaptic pathology in the limbic system may be of importance in the development of psychotic symptoms in schizophrenia.
精神分裂症是一种病因不明的常见且严重的精神障碍。众多神经病理学研究发现边缘系统存在细微的结构变化，尤其是内侧颞叶结构和扣带回。为了验证突触紊乱参与精神分裂症发病机制这一假说，我们使用定量蛋白质免疫印迹法免疫组织化学技术，研究了生长相关蛋白43（GAP - 43），一种定位于突触前终末的蛋白质，推测其参与突触连接的建立和重塑，该研究以死后脑组织为对象。研究材料包括17例精神分裂症患者（80±11岁）的脑组织，依据DSM - III - R标准进行诊断，以及20例年龄匹配的对照者（75±13岁）的脑组织。定量分析显示，与对照脑相比，精神分裂症患者脑内海马体（2.43±0.78对1.00±0.29；p<0.0001）和扣带回（1.52±0.21对1.00±0.35；p<．0001）中GAP - 43蛋白水平均升高。同样通过免疫组织化学发现，与对照脑相比，精神分裂症患者脑内扣带回和海马体各层均出现GAP - 43染色增强。异常的突触发芽和重组，以及由此导致的“错连”，还有突触修剪缺陷，均被认为是精神分裂症的致病因素。我们认为，无论是发育紊乱还是损伤/退变导致的突触密度降低，都可能引发反应性突触再生（以GAP - 43增加为体现），这可能是功能性的，也可能是异常的。边缘系统的突触病理学在精神分裂症精神病性症状的发生发展中可能具有重要意义。
