Zimmer L A, Ennis M, Shipley M T
Department of Anatomy, University of Maryland School of Medicine, Baltimore 21201, USA.
J Comp Neurol. 1997 Feb 24;378(4):482-92. doi: 10.1002/(sici)1096-9861(19970224)378:4<482::aid-cne4>3.0.co;2-z.
Neurons in the piriform cortex and the pontine nucleus locus coeruleus express elevated levels of the immediate early gene protein product, Fos, within 30-45 minutes of a seizurogenic dose of the anticholinesterase, soman (Zimmer et al., [1997] J. Comp. Neurol. 378:468-481). By 24 hours following soman injection, there is marked neuropathology in the piriform cortex. These findings suggest selective, regional vulnerability in response to the seizurogenic actions of soman. In the present study, we determined that soman-induced seizures also cause selective, rapid activation of astrocytes and microglia in the piriform cortex and other brain regions. Animals were killed at different intervals between 1 hour and 24 hours after a convulsive dose of soman. Brain sections were processed for immunocytochemical detection of astrocytes with antibodies against glial fibrillary acidic protein, and microglia and macrophages with antibodies against the complement receptor 3 protein, OX-42. The results demonstrate that following soman administration: (1) there is a rapid increase in glial fibrillary acidic protein staining in astrocytes of the piriform cortex (1 hour); (ii) reactive astrocytes are specifically restricted to layer II and the superficial boundaries of layer III of the piriform cortex. These are the same layers in which neurons express Fos within 30-45 minutes following soman administration; (3) between 1 and 4 hours, resting (ramified) microglia in the piriform cortex and the hippocampus alter their morphology to resemble active microglia. From 4-8 hours, active microglia undergo morphological changes characteristic of reactive microglia that resemble macrophages. Taken together, these observations indicate that astrocytes and microglia in brain regions susceptible to soman become rapidly "reactive" in response to seizures. The highly specific anatomical codistribution of reactive glia and Fos-expressing neurons suggests that intensely active neurons provide local signals that trigger reactive changes in neighboring glia.
在给予致痫剂量的抗胆碱酯酶药物梭曼后30 - 45分钟内，梨状皮质和脑桥核蓝斑中的神经元表达即刻早期基因蛋白产物Fos的水平升高（齐默等人，[1997]《比较神经学杂志》378:468 - 481）。梭曼注射后24小时，梨状皮质出现明显的神经病理学改变。这些发现表明，在对梭曼的致痫作用的反应中存在选择性的区域易损性。在本研究中，我们确定梭曼诱发的癫痫发作还会导致梨状皮质和其他脑区的星形胶质细胞和小胶质细胞选择性、快速激活。在给予惊厥剂量的梭曼后，于1小时至24小时的不同时间间隔处死动物。脑切片用抗胶质纤维酸性蛋白抗体进行免疫细胞化学检测星形胶质细胞，用抗补体受体3蛋白OX - 42抗体检测小胶质细胞和巨噬细胞。结果表明，给予梭曼后：(1)梨状皮质星形胶质细胞中的胶质纤维酸性蛋白染色迅速增加（1小时）；(ii)反应性星形胶质细胞特异性地局限于梨状皮质的II层和III层的浅层边界。这些是在给予梭曼后30 - 45分钟内神经元表达Fos的相同层；(3)在1至4小时之间，梨状皮质和海马中的静息（分支状）小胶质细胞改变其形态，类似于活化的小胶质细胞。从4至8小时，活化的小胶质细胞经历类似于巨噬细胞的反应性小胶质细胞的形态变化。综上所述，这些观察结果表明，易受梭曼影响的脑区中的星形胶质细胞和小胶质细胞会因癫痫发作而迅速“反应性”增强。反应性胶质细胞与表达Fos的神经元高度特异性的解剖共分布表明，高度活跃的神经元提供局部信号，触发邻近胶质细胞的反应性变化。
