Wang C, Anastasio N, Popov V, Leday A, Johnson K M
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555-1031, USA.
Neuroscience. 2004;125(2):473-83. doi: 10.1016/j.neuroscience.2004.02.003.
Perinatal administration of the N-methyl-Dd-aspartate (NMDA) receptor antagonist phencyclidine (PCP) has been reported to produce regionally selective apoptotic cell death in the frontal cortex. The development of certain behavioral abnormalities following PCP treatment suggested that extracortical regions such as the striatum also could be affected. In this study, perinatal PCP treatment caused a marked reduction in striatal, but not hippocampal, staining for polysialic acid-neural cell adhesion molecule (PSA-NCAM), an NMDA-regulated molecule important in synaptogenesis. In order to isolate striatal influences to the cortex, this investigation was continued in vitro using corticostriatal slices. For these experiments we cultured coronal corticostriatal slices from postnatal day 7 rats. After 4 days in vitro, PCP was added for 48 h and then washed out for 24 h before harvesting the tissue. Similar to what was observed in vivo, we found that PCP treatment results in a marked reduction in striatal staining for PSA-NCAM. No change was observed in the mature form of NCAM. In striatal synaptoneurosomes, immunoblot analysis confirmed that the levels of PSA-NCAM and synaptophysin, a molecule often used as a marker of synaptogenesis, were substantially down-regulated by PCP. These effects were prevented by M40403, a superoxide dismutase mimetic that also prevented the PCP-induced terminal dUTP nick-end labeling of DNA fragments that was observed selectively in the cortex. These data suggest that PCP causes cell death by apoptosis selectively in the cortex, but not in the striatum, following either in vivo treatment of perinatal rat pups or in vitro treatment of corticostriatal slices. Further, cortical apoptosis induced by PCP negatively impacts striatal synaptogenesis, a process important in normal neural development. This deficit is probably caused by a reduction in corticostriatal neurotransmission. It is possible that the dysregulation of striatal synaptogenesis contributes to the behavioral abnormalities observed following perinatal PCP administration in vivo.
据报道，围产期给予N-甲基-D-天冬氨酸（NMDA）受体拮抗剂苯环己哌啶（PCP）会在额叶皮质产生区域选择性凋亡性细胞死亡。PCP治疗后某些行为异常的出现表明，纹状体等皮质外区域也可能受到影响。在本研究中，围产期PCP治疗导致纹状体中多唾液酸神经细胞黏附分子（PSA-NCAM，一种在突触形成中起重要作用的NMDA调节分子）的染色显著减少，但海马体中未出现这种情况。为了分离纹状体对皮质的影响，本研究继续在体外使用皮质纹状体切片进行。对于这些实验，我们培养了出生后第7天大鼠的冠状皮质纹状体切片。在体外培养4天后，加入PCP处理48小时，然后在收获组织前冲洗24小时。与体内观察到的情况相似，我们发现PCP处理导致纹状体中PSA-NCAM的染色显著减少。未观察到NCAM成熟形式的变化。在纹状体突触小体中，免疫印迹分析证实，PCP使PSA-NCAM和突触素（一种常用作突触形成标志物的分子）的水平大幅下调。超氧化物歧化酶模拟物M40403可预防这些效应，它还能预防PCP诱导的DNA片段末端脱氧尿苷三磷酸缺口末端标记，这种标记在皮质中被选择性观察到。这些数据表明，无论是对围产期幼鼠进行体内治疗，还是对皮质纹状体切片进行体外治疗，PCP都会选择性地在皮质而非纹状体中通过凋亡导致细胞死亡。此外，PCP诱导的皮质凋亡对纹状体突触形成产生负面影响，而突触形成在正常神经发育中很重要。这种缺陷可能是由皮质纹状体神经传递减少引起的。纹状体突触形成失调可能导致围产期在体内给予PCP后观察到的行为异常。
