Chronic epileptogenic cellular alterations in the limbic system after status epilepticus
Chronic epileptogenic cellular alterations in the limbic system after status epilepticus
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DOI：
10.1111/j.1528-1157.1999.tb00875.x
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发表时间：
1999-01-01
期刊：
影响因子：
5.6
通讯作者：
Coulter, DA
中科院分区：
文献类型：
--
作者：
Coulter, DA
癫痫持续状态(SE)既有急性后遗症，也有永久性的病理后遗症。SE的一个常见的长期后果是随后发展为慢性癫痫，癫痫发作经常起源于边缘系统并累及边缘系统。在SE后，许多研究表明选择性地丢失了齿状回门区内的神经元，即CA1和CA3锥体神经元。海马区不同的中间神经元亚群的选择性丢失也经常是明显的，尽管中间神经元作为一个整体相对于主细胞选择性地幸免。伴随这种神经元丢失的是回路重排，最广泛研究的是齿状颗粒细胞(DGC)轴突发芽回到齿状回内分子层，称为苔藓纤维发芽。癫痫发作后，癫痫海马区存活神经元的受体特性研究较少。癫痫动物体内的DGC表现出明显的伽马氨基丁酸(GABA)受体功能和药理特性的改变。在慢性癫痫动物中，DGC的GABA(A)受体密度显著升高。此外，癫痫后癫痫动物的GABA受体的药理特性与对照组有很大的不同。特别是，癫痫动物DGC中的GABA(A)受体对锌的阻断敏感性增强，对苯二氮卓类药物的调节敏感性显著改变。这些药理差异可能是由于癫痫后癫痫动物DGC中GABA(A)受体α1亚基相对其他α亚基的表达减少所致。这些GABA(A)受体的改变先于SE后DGCs的自发性癫痫发作，因此在时间上对边缘系统的癫痫发生过程有贡献。对锌敏感的GABA受体的存在，以及癫痫发作后海马区DGCs近侧树突的含锌苔藓纤维终末的存在，促进了癫痫脑中DG的重复激活可能导致锌的释放的假说的发展。这种锌反过来可能扩散到并阻断DGC中对锌敏感的GABA(A)受体，导致癫痫发作后边缘系统的抑制灾难性失败，并伴随着癫痫发作倾向的增强。
Status epilepticus (SE) is associated with both acute and permanent pathological sequellae. One common long term consequence of SE is the subsequent development of a chronic epileptic condition, with seizures frequently originating from and involving the limbic system. Following SE, many studies have demonstrated selective loss of neurons-within the hilar region of the dentate gyms, CA1 and CA3 pyramidal neurons. Selective loss of distinct subpopulations of interneurons throughout the hippocampus is also frequently evident, although interneurons as a whole are selectively spared relative to principal cells. Accompanying this loss of neurons are circuit rearrangements, the most widely studied being the sprouting of dentate granule cell (DGC) axons back onto the inner molecular layer of the dentate gyrus, termed mossy fiber sprouting. Less studied are the receptor properties of the surviving neurons within the epileptic hippocampus following SE. DGCs in epileptic animals exhibit marked alterations in the functional and pharmacological properties of gamma-aminobutyric acid (GABA) receptors. DGCs have a significantly elevated density of GABA(A) receptors in chronically epileptic animals. In addition, the pharmacological properties of GABA, receptors in post-SE epileptic animals are quite different compared to controls. In particular, GABA(A) receptors in DGCs from epileptic animals show an enhanced sensitivity to blockade by zinc, and a markedly altered sensitivity to modulation by benzodiazepines. These pharmacological differences may be due to a decreased expression of alpha 1 subunits of the GABA(A) receptor relative to other a subunits in DGCs of post-SE epileptic animals. These GABA(A) receptor alterations precede the onset of spontaneous seizures in post-SE DGCs, and so are temporally positioned to contribute to the process of epileptogenesis in the limbic system. The presence of zinc sensitive GABA receptors combined with the presence of zinc-containing "sprouted" mossy fiber terminals innervating the proximal dendrites of DGCs in the post-SE epileptic hippocampus prompted the development of the hypothesis that repetitive activation of the DG in the epileptic brain could result in the release of zine. This zinc in turn may diffuse to and block "epileptic" zinc-sensitive GABA(A) receptors in DGCs, leading to a catastrophic failure of inhibition and concomitant enhanced seizure propensity in the post-SE epileptic limbic system.