Aquaporin 4 knockout resists negative regulation of neural cell proliferation by cocaine in mouse hippocampus
Aquaporin 4 knockout resists negative regulation of neural cell proliferation by cocaine in mouse hippocampus
复制标题
水通道蛋白 4 敲除可抵抗可卡因对小鼠海马神经细胞增殖的负调节
DOI：
10.1017/s1461145709009900
复制
发表时间：
2009-07-01
影响因子：
4.8
通讯作者：
Hu, Gang
中科院分区：
文献类型：
--
作者：
Xie, Lu-Lu;Sun, Xiu-Lan;Hu, Gang
我们之前的研究发现，敲除aquaporin 4 （AQP4）可降低可卡因暴露小鼠的运动活性，降低伏隔核细胞外多巴胺水平，提示AQP4可能参与可卡因成瘾。本研究旨在探讨AQP4对反复可卡因治疗和停药后小鼠海马齿状回细胞增殖的影响。免疫组化结果显示，反复给药可显著降低颗粒下区细胞增殖，停药2周后出现反弹，停药3周后恢复正常。AQP4敲除可抵抗可卡因诱导的神经细胞增殖减少。通过免疫组织化学和免疫印迹分析进一步研究表明，敲除AQP4可维持海马胶质原纤维酸性蛋白水平，并抑制重复给药引起的细胞外信号调节激酶磷酸化的增强。值得注意的是，通过底物蛋白磷酸化法检测，AQP4敲除增加了蛋白激酶C的活性，而这一活性不受可卡因给药或停药的影响。我们还发现，在野生型小鼠中，反复给药可提高AQP4的表达。综上所述，本研究首次报道了AQP4基因敲除通过上调pkc介导的信号转导来抵抗可卡因介导的神经细胞增殖抑制，提示AQP4可能调控吸毒期间的神经发生。我们的发现可能对神经发生的细胞生物学有帮助。
Our previous study revealed that aquaporin 4 (AQP4) knockout attenuated locomotor activity in cocaine exposure mice and reduced the extracellular dopamine levels in the nucleus accumbens, suggesting that AQP4 might participate in cocaine addiction. The aim of the present study was to investigate the impact of AQP4 on cell proliferation of dentate gyrus in the Mouse hippocampus after repeated cocaine treatment and withdrawal. The immunohistochemistry results showed that repeated cocaine administration significantly decreased cellular proliferation in the subgranular zone, which was followed by a rebound increase after 2-wk withdrawal and a return to normal level after 3-wk withdrawal. AQP4 knockout resisted cocaine-induced reductions of neural cell proliferation. Further studies through immunohistochemistry and immunoblot analysis showed that AQP4 knockout sustained the levels of glial fibrillary acidic protein in the hippocampus, and suppressed the enhancement of extracellular signal-regulated kinase phosphorylation induced by repeated cocaine administration. Notably, AQP4 knockout increased protein kinase C activity examined by substrate protein phosphorylation method, which was not affected by cocaine administration or withdrawal. We also found that repeated cocaine administration could elevate the expression of AQP4 in wild-type mice. In conclusion, it is reported for the first time that AQP4 knockout resisted cocaine-mediated inhibition of neural cell proliferation via up-regulating PKC-mediated signal transduction, suggesting that AQP4 might regulate neurogenesis during drug addiction. Our findings may have helpful implications in the cell biology of neurogenesis.