Roles of Astrocytes and Microglia in Seizure-Induced Aberrant Neurogenesis in the Hippocampus of Adult Rats
Roles of Astrocytes and Microglia in Seizure-Induced Aberrant Neurogenesis in the Hippocampus of Adult Rats
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DOI：
10.1002/jnr.22224
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发表时间：
2010-02-15
影响因子：
4.2
通讯作者：
Jiang, Wen
中科院分区：
文献类型：
--
作者：
Yang, Fang;Liu, Zhi-Rong;Jiang, Wen
最近的证据表明，癫痫发作增加成年大鼠海马神经发生，但长时间的癫痫发作导致异常的海马神经发生，往往导致反复兴奋性回路，从而有助于癫痫发生。然而，长期癫痫发作后异常神经发生的机制仍不清楚。在这项研究中，我们研究了活化的星形胶质细胞和小胶质细胞在癫痫持续状态诱导的海马神经发生异常中的作用。使用锂-匹罗卡品模型来模拟人类颞叶癫痫，我们发现癫痫持续状态诱导了首次癫痫发作后3、7、14和20天齿状回星形胶质细胞和小胶质细胞的显著激活。然后，我们立体定向注射fluorocitrate到齿状门抑制星形胶质细胞的代谢，发现fluorocitrate未能防止异位门基底树突的形成，而是促进癫痫发作后齿状颗粒细胞的变性。相反，选择性抑制剂的小胶质细胞活化，米诺环素，抑制异常迁移的新生神经元在癫痫持续状态后14天。此外，立体定位注射脂多糖到完整的齿状门激活当地的小胶质细胞，我们发现，脂多糖促进异位门基底树突在海马的发展。这些结果表明，激活的小胶质细胞在癫痫门可以引导异常迁移的新生神经元和米诺环素可能是一种潜在的药物，以阻止癫痫诱导的异常迁移的新生神经元。(C)2009 Wiley-Liss，Inc.
Recent evidence showed that epileptic seizures increase hippocampal neurogenesis in the adult rat, but prolonged seizures result in the aberrant hippocampal neurogenesis that often leads to a recurrent excitatory circuitry and thus contributes to epileptogenesis. However, the mechanism underlying the aberrant neurogenesis after prolonged seizures remains largely unclear. In this study, we examined the role of activated astrocytes and microglia in the aberrant hippocampal neurogenesis induced by status epilepticus. Using a lithium-pilocarpine model to mimic human temporal lobe epilepsy, we found that status epilepticus induced a prominent activation of astrocytes and microglia in the dentate gyrus 3, 7, 14, and 20 days after the initial seizures. Then, we injected fluorocitrate stereotaxicly into the dentate hilus to inhibit astrocytic metabolism and found that fluorocitrate failed to prevent the seizure-induced formation of ectopic hilar basal dendrites but instead promoted the degeneration of dentate granule cells after seizures. In contrast, a selective inhibitor of microglia activation, minocycline, inhibited the aberrant migration of newborn neurons at 14 days after status epilepticus. Furthermore, with stereotaxic injection of lipopolysaccharide into the intact dentate hilus to activate local microglia, we found that lipopolysaccharide promoted the development of ectopic hilar basal dendrites in the hippocampus. These results indicate that the activated microglia in the epileptic hilus may guide the aberrant migration of newborn neurons and that minocycline could be a potential drug to impede seizure-induced aberrant migration of newborn neurons. (C) 2009 Wiley-Liss, Inc.