Rapamycin inhibits mTOR/p70S6K activation in CA3 region of the hippocampus of the rat and impairs long term memory.
Rapamycin inhibits mTOR/p70S6K activation in CA3 region of the hippocampus of the rat and impairs long term memory.
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DOI：
10.1016/j.nlm.2016.11.006
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发表时间：
2017-01
影响因子：
2.7
通讯作者：
Giovannini, M. G.
中科院分区：
文献类型：
--
作者：
Lana, D.;Di Russo, J.;Mello, T.;Wenk, G. L.;Giovannini, M. G.
本研究的目的是建立是否mTOR通路及其下游效应p70 S6 K在CA 3锥体神经元的胆碱能输入的调制下，触发长期记忆的形成，类似于我们在CA 1海马证实。我们在成年Wistar大鼠上进行了在体行为学实验，使用步下抑制回避实验来评估不同条件下的记忆形成。我们研究了雷帕霉素（mTORC 1形成抑制剂）、东莨菪碱（毒蕈碱受体拮抗剂）或美加明（烟碱受体拮抗剂）对短期和长期记忆形成以及mTOR通路功能的影响。在i. c. v.注射雷帕霉素后30分钟进行采集。在采集后1小时、4小时或24小时进行回忆测试。结果发现：（1）海马CA 3区锥体神经元mTOR和p70 S6 K的激活参与了长时程记忆的形成，（2）雷帕霉素在4 h显著抑制mTOR和p70 S6 K的激活，在24 h显著抑制长时程记忆损害;（3）东莨菪碱损害短时记忆，但不损害长时记忆，mTOR/p70 S6 K激活在1h早期增加，随后在较长时间内稳定;（4）美卡拉明和东莨菪碱联合给药在1h和4 h损害短期记忆，并减少东莨菪碱诱导的mTOR/mTOR增加。在1小时和4小时的p70 S6 K活化;（5）美加明和东莨菪碱处理不损害长期记忆形成;（6）出乎意料地，雷帕霉素增加小胶质细胞中的mT 0 RC 2活化。我们的研究结果表明，在CA 3锥体神经元的mTOR/p70 S6 K通路的胆碱能系统的调制下，并参与长期记忆编码，并与海马CA 3区参与记忆机制的基础上快速，一次试验对象-位置学习和回忆的假设是一致的。此外，我们的研究结果与以前的报道一致，即选择性分子机制是短期记忆，长期记忆或两者兼而有之的基础。此外，我们发现给予雷帕霉素增加了小胶质细胞中mTORC 2的活化，这支持了对给予雷帕霉素的有益/不利影响的重新评估。
The present study was aimed at establishing whether the mTOR pathway and its downstream effector p70S6K in CA3 pyramidal neurons are under the modulation of the cholinergic input to trigger the formation of long term memories, similar to what we demonstrated in CA1 hippocampus. We performed in vivo behavioral experiments using the step down inhibitory avoidance test in adult Wistar rats to evaluate memory formation under different conditions. We examined the effects of rapamycin, an inhibitor of mTORC1 formation, scopolamine, a muscarinic receptor antagonist or mecamylamine, a nicotinic receptor antagonist, on short and long term memory formation and on the functionality of the mTOR pathway. Acquisition was conducted 30 min after i.c.v. injection of rapamycin. Recall testing was performed 1h, 4h or 24h after acquisition. We found that (1) mTOR and p70S6K activation in CA3 pyramidal neurons were involved in long term memory formation; (2) rapamycin significantly inhibited mTOR and of p70S6K activation at 4h, and long term memory impairment 24h after acquisition; (3) scopolamine impaired short but not long term memory, with an early increase of mTOR/p70S6K activation at 1h followed by stabilization at longer times; (4) mecamylamine and scopolamine co-administration impaired short term memory at 1h and 4h and reduced the scopolamine-induced increase of mTOR/p70S6K activation at 1h and 4h; (5) mecamylamine and scopolamine treatment did not impair long term memory formation; (6) unexpectedly, rapamycin increased mTORC2 activation in microglial cells. Our results demonstrate that in CA3 pyramidal neurons the mTOR/p70S6K pathway is under the modulation of the cholinergic system and is involved in long-term memory encoding, and are consistent with the hypothesis that the CA3 region of the hippocampus is involved in memory mechanisms based on rapid, one-trial object–place learning and recall. Furthermore, our results are in accordance with previous reports that selective molecular mechanisms underlie either short term memory, long term memory, or both. Furthermore, our discovery that administration of rapamycin increased the activation of mTORC2 in microglial cells supports a reappraisal of the beneficial/adverse effects of rapamycin administration.
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DOI：
10.1083/jcb.200403069
发表时间：
2004-07-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Harrington LS;Findlay GM;Gray A;Tolkacheva T;Wigfield S;Rebholz H;Barnett J;Leslie NR;Cheng S;Shepherd PR;Gout I;Downes CP;Lamb RF
通讯作者：
Lamb RF
影响因子：
2.7
作者：
Giovannini, MG;Bartolini, L;Blandina, P
通讯作者：
Blandina, P
影响因子：
2.7
作者：
Bekinschtein, Pedro;Katche, Cynthia;Medina, Jorge H.
通讯作者：
Medina, Jorge H.
影响因子：
16.2
作者：
Hoeffer, Charles A.;Tang, Wei;Klann, Eric
通讯作者：
Klann, Eric
DOI：
10.4161/cc.8.7.8044
发表时间：
2009-04-01
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Foster DA;Toschi A
通讯作者：
Toschi A