Effects of Rapamycin Treatment on Neurogenesis and Synaptic Reorganization in the Dentate Gyrus after Controlled Cortical Impact Injury in Mice.
Effects of Rapamycin Treatment on Neurogenesis and Synaptic Reorganization in the Dentate Gyrus after Controlled Cortical Impact Injury in Mice.
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DOI：
10.3389/fnsys.2015.00163
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发表时间：
2015
影响因子：
3
通讯作者：
Smith BN
中科院分区：
文献类型：
--
作者：
Butler CR;Boychuk JA;Smith BN
创伤后癫痫（PTE）是创伤性脑损伤（TBI）的后果之一。在TBI和癫痫的动物模型中激活的一个突出的细胞信号传导途径是雷帕霉素的哺乳动物靶点（mTOR）。雷帕霉素抑制mTOR在几种癫痫动物模型中显示出作为癫痫发生的潜在调节剂的前景，但将mTOR表达与癫痫发生联系起来的细胞机制尚不清楚。在这项研究中，mTOR的作用，修改功能海马电路重组后，局灶性TBI诱导的控制性皮质撞击（CCI）进行了调查。雷帕霉素（3或10 mg/kg），一种mTOR信号传导的抑制剂，从损伤当天开始通过腹膜内注射施用，并且每天持续直至组织收集。相对于对照组，雷帕霉素治疗减少了损伤后两周损伤同侧半球的齿状颗粒细胞面积。脑损伤导致损伤同侧齿状回双皮质素免疫标记显著增加，表明TBI后不久神经发生增加。雷帕霉素治疗阻止了双皮质素标记的增加，对同侧半球的Fluoro-Jade B染色没有总体影响，表明雷帕霉素治疗减少了创伤后神经发生，但不能防止损伤后细胞丢失。在损伤后的较晚时间（8-13周），检测到苔藓纤维发芽和齿状颗粒细胞的复发性兴奋增加的证据，其被雷帕霉素处理减弱。雷帕霉素治疗也减少了癫痫发作的患病率相对于车辆处理的对照组TBI后。总的来说，这些结果支持成人神经发生在PTE发展中的作用，并表明mTOR抑制对癫痫发生的抑制包括对损伤后神经发生的影响。
Post-traumatic epilepsy (PTE) is one consequence of traumatic brain injury (TBI). A prominent cell signaling pathway activated in animal models of both TBI and epilepsy is the mammalian target of rapamycin (mTOR). Inhibition of mTOR with rapamycin has shown promise as a potential modulator of epileptogenesis in several animal models of epilepsy, but cellular mechanisms linking mTOR expression and epileptogenesis are unclear. In this study, the role of mTOR in modifying functional hippocampal circuit reorganization after focal TBI induced by controlled cortical impact (CCI) was investigated. Rapamycin (3 or 10 mg/kg), an inhibitor of mTOR signaling, was administered by intraperitoneal injection beginning on the day of injury and continued daily until tissue collection. Relative to controls, rapamycin treatment reduced dentate granule cell area in the hemisphere ipsilateral to the injury two weeks post-injury. Brain injury resulted in a significant increase in doublecortin immunolabeling in the dentate gyrus ipsilateral to the injury, indicating increased neurogenesis shortly after TBI. Rapamycin treatment prevented the increase in doublecortin labeling, with no overall effect on Fluoro-Jade B staining in the ipsilateral hemisphere, suggesting that rapamycin treatment reduced posttraumatic neurogenesis but did not prevent cell loss after injury. At later times post-injury (8–13 weeks), evidence of mossy fiber sprouting and increased recurrent excitation of dentate granule cells was detected, which were attenuated by rapamycin treatment. Rapamycin treatment also diminished seizure prevalence relative to vehicle-treated controls after TBI. Collectively, these results support a role for adult neurogenesis in PTE development and suggest that suppression of epileptogenesis by mTOR inhibition includes effects on post-injury neurogenesis.