Rapamycin reverses status epilepticus-induced memory deficits and dendritic damage.
Rapamycin reverses status epilepticus-induced memory deficits and dendritic damage.
复制标题
DOI：
10.1371/journal.pone.0057808
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Anderson AE
中科院分区：
文献类型：
--
作者：
Brewster AL;Lugo JN;Patil VV;Lee WL;Qian Y;Vanegas F;Anderson AE
认知障碍是人类和动物模型长期持续癫痫发作(癫痫持续状态；SE)的显著后遗症。虽然经常与树突状细胞损伤有关，但潜在的机制仍然难以捉摸。雷帕霉素复合体1(MTORC1)通路的哺乳动物靶点在SE后被过度激活。这一途径调节学习和记忆，并与神经元、树突和神经胶质属性的调节有关。因此，在目前的研究中，我们检验了SE诱导的mTORC1过度激活是SE后认知障碍和树突状病变的候选机制的假设。我们研究了mTORC1抑制剂雷帕霉素对匹罗卡品诱导的SE发作相关的早期海马区依赖的空间学习和记忆障碍的影响。雷帕霉素治疗的SE大鼠在Morris水迷宫和新物体识别测试这两个空间记忆任务中的表现明显好于赋形剂治疗的大鼠。在分子水平上，我们发现SE诱导的mTORC1信号的增加定位于神经元和小胶质细胞。雷帕霉素降低SE诱导的mTOR激活，减轻小胶质细胞增生，主要定位于CA1区。这些发现与雷帕霉素治疗后SE诱导的树突状MAP2和离子通道水平的下降以及树突分支和CA1区棘突密度的改善是平行的。综上所述，这些发现表明，mTORC1过度活动导致早期海马依赖的空间学习和记忆缺陷，以及与SE相关的树突调节障碍。
Cognitive impairments are prominent sequelae of prolonged continuous seizures (status epilepticus; SE) in humans and animal models. While often associated with dendritic injury, the underlying mechanisms remain elusive. The mammalian target of rapamycin complex 1 (mTORC1) pathway is hyperactivated following SE. This pathway modulates learning and memory and is associated with regulation of neuronal, dendritic, and glial properties. Thus, in the present study we tested the hypothesis that SE-induced mTORC1 hyperactivation is a candidate mechanism underlying cognitive deficits and dendritic pathology seen following SE. We examined the effects of rapamycin, an mTORC1 inhibitor, on the early hippocampal-dependent spatial learning and memory deficits associated with an episode of pilocarpine-induced SE. Rapamycin-treated SE rats performed significantly better than the vehicle-treated rats in two spatial memory tasks, the Morris water maze and the novel object recognition test. At the molecular level, we found that the SE-induced increase in mTORC1 signaling was localized in neurons and microglia. Rapamycin decreased the SE-induced mTOR activation and attenuated microgliosis which was mostly localized within the CA1 area. These findings paralleled a reversal of the SE-induced decreases in dendritic Map2 and ion channels levels as well as improved dendritic branching and spine density in area CA1 following rapamycin treatment. Taken together, these findings suggest that mTORC1 hyperactivity contributes to early hippocampal-dependent spatial learning and memory deficits and dendritic dysregulation associated with SE.
登录
查看更多内容
影响因子：
56.9
作者：
Bernard, C;Anderson, A;Johnston, D
通讯作者：
Johnston, D
影响因子：
6.1
作者：
Erlich, S.;Alexandrovich, A.;Pinkas-Kramarski, R.
通讯作者：
Pinkas-Kramarski, R.
影响因子：
4.8
作者：
Fenoglio, KA;Brunson, KL;Baram, TZ
通讯作者：
Baram, TZ
影响因子：
5.3
作者：
Jung, Sangwook;Jones, Terrance D.;Poolos, Nicholas P.
通讯作者：
Poolos, Nicholas P.
影响因子：
4.8
作者：
Gong, Ruomu;Park, Chang Sin;Tang, Shao-Jun
通讯作者：
Tang, Shao-Jun