The mammalian target of rapamycin signaling pathway mediates epileptogenesis in a model of temporal lobe epilepsy.
The mammalian target of rapamycin signaling pathway mediates epileptogenesis in a model of temporal lobe epilepsy.
复制标题
DOI：
10.1523/jneurosci.0066-09.2009
复制
发表时间：
2009-05-27
期刊：
影响因子：
--
通讯作者：
Wong M
中科院分区：
文献类型：
--
作者：
Zeng LH;Rensing NR;Wong M
Understanding molecular mechanisms mediating epileptogenesis is critical for developing more effective therapies for epilepsy. We recently found that the mammalian target of rapamycin (mTOR) signaling pathway is involved in epileptogenesis and mTOR inhibitors prevent epilepsy in a mouse model of Tuberous Sclerosis Complex. Here, we investigated the potential role of mTOR in a rat model of temporal lobe epilepsy initiated by status epilepticus. Acute kainate-induced seizures resulted in biphasic activation of the mTOR pathway, as evident by an increase in phosopho-S6 (P-S6) expression. An initial rise in P-S6 expression started about one hour after seizure onset, peaked at 3-6 hours and returned to baseline by 24 hours in both hippocampus and neocortex, reflecting widespread stimulation of mTOR signaling by acute seizure activity. Following resolution of status epilepticus, a second increase in P-S6 was observed in hippocampus only, which started at 3 days, peaked 5-10 days, and persisted for several weeks after kainate injection, correlating with the development of chronic epileptogenesis within hippocampus. The mTOR inhibitor, rapamycin, administered prior to kainate blocked both the acute and chronic phases of seizure-induced mTOR activation and decreased kainate-induced neuronal cell death, neurogenesis, mossy fiber sprouting, and the development of spontaneous epilepsy. Late rapamycin treatment, after termination of status epilepticus, blocked the chronic phase of mTOR activation and reduced mossy fiber sprouting and epilepsy, but not neurogenesis or neuronal death. These findings indicate that mTOR signaling mediates mechanisms of epileptogenesis in the kainate rat model and mTOR inhibitors have potential anti-epileptogenic effects in this model.
