Centre for Psychiatric Neuroscience, Lausanne, Switzerland.
J Anat. 2010 Oct;217(4):324-33. doi: 10.1111/j.1469-7580.2010.01231.x.
Schizophrenia probably has a developmental origin. This review refers to three of our published series of studies related to this hypothesis: loss of dendritic spines on cerebral neocortical pyramidal neurons, decreased numerical density of glutamatergic neurons, and microgliosis. First, brains of schizophrenic patients and non-schizophrenic controls were obtained post mortem and blocks of multiple cortical areas impregnated with a Rapid Golgi method. Spines were counted on the dendrites of pyramidal neurons of which the soma was in layer III (which takes part in corticocortical connectivity) and which met strict criteria for impregnation quality. Data were obtained blind: diagnoses were only revealed by a third party after measurements were completed. The mean spine count in all cortical areas studied in the control series was 243 mm(-1) of dendrite and in the schizophrenics 108. Measurements in frontal and temporal association cortex showed the greatest reduction in spine number in schizophrenia (299 in control frontal cortex and 101 in schizophrenics, and 276 mm(-1) in control temporal cortex and 125 in schizophrenics). There was no correlation of spine loss with age at death. Our results support the concept of a neurodevelopmental defect in the neuropil affecting glutamatergic neurons in schizophrenia and may help to explain loss of cortical volume without loss of neurons. In a second part of our study we used an antibody to the kainate receptor subunit GluR 5/6/7 and showed a decrease in numerical density of presumed glutamatergic neurons in schizophrenic orbitofrontal cortex. Finally, as glia play a major role in the developing nervous system, we investigated whether schizophrenia was associated with glial changes in frontal and temporal cortex. Astroglia and microglia were identified in schizophrenic and control brains, using antibodies to glial fibrillary acidic protein (GFAP) and class II human leucocyte antigen (HLA-DR), respectively. Significant increases were found in microglial numerical density in schizophrenics compared with controls: 28% in frontal area 9 (115 cells mm(-2) compared with 89), and a 57% increase in temporal area 22 (139 cells mm(-2) compared with 88). For both areas, astroglia showed no significant differences between schizophrenics and controls. No significant differences were found in cortical thickness or total neuronal numerical density between the two groups. This specific increase in numerical density of microglia in temporal and frontal cortex of chronic schizophrenics, not related to aging, could be related to possible changes in cortical neuropil architecture as revealed by loss of dendritic spines.
精神分裂症可能具有发育起源。本综述提到了我们已发表的三个与该假说相关的系列研究：大脑新皮质锥体神经元树突棘丢失、谷氨酸能神经元数量密度降低和小胶质细胞增生。首先，我们从死后的精神分裂症患者和非精神分裂症对照者大脑中获得多个皮质区的组织块，并用 Rapid Golgi 方法进行处理。对树突棘的计数是在锥体神经元的树突上进行的，其胞体位于第 III 层（参与皮质间连接），且满足严格的处理质量标准。数据是在盲法条件下获得的：只有在测量完成后，第三方才能揭示诊断结果。在对照组的所有研究皮质区中，树突上的平均棘突数为 243 个/mm(-1)，而在精神分裂症患者中为 108 个/mm(-1)。在额颞联合皮质区的测量结果显示，精神分裂症患者的棘突数量减少最多（对照组额皮质为 299 个/mm(-1)，精神分裂症患者为 101 个/mm(-1)；对照组颞皮质为 276 个/mm(-1)，精神分裂症患者为 125 个/mm(-1)）。棘突丢失与死亡时的年龄无相关性。我们的结果支持神经发育缺陷的概念，该缺陷影响精神分裂症神经突中的谷氨酸能神经元，可能有助于解释皮质体积减少而神经元数量不变的现象。在我们研究的第二部分中，我们使用了一种针对 kainate 受体亚基 GluR 5/6/7 的抗体，并显示出精神分裂症患者眶额皮质中假定谷氨酸能神经元数量密度降低。最后，由于神经胶质在发育中的神经系统中起主要作用，我们研究了精神分裂症是否与额颞皮质中的神经胶质变化有关。使用针对神经胶质纤维酸性蛋白 (GFAP) 和 II 类人类白细胞抗原 (HLA-DR) 的抗体，分别鉴定出精神分裂症和对照组大脑中的星形胶质细胞和小胶质细胞。与对照组相比，精神分裂症患者的小胶质细胞数量密度显著增加：额皮质 9 区增加 28%（115 个细胞/mm(-2)比 89），颞皮质 22 区增加 57%（139 个细胞/mm(-2)比 88）。对于这两个区域，星形胶质细胞在精神分裂症患者和对照组之间没有显著差异。两组之间的皮质厚度或总神经元数量密度没有显著差异。慢性精神分裂症患者颞叶和额叶皮质中这种特定的小胶质细胞数量密度的增加（与年龄无关）可能与树突棘丢失所揭示的皮质神经突结构的可能变化有关。
