5-HT(6) receptor recruitment of mTOR as a mechanism for perturbed cognition in schizophrenia.
5-HT(6) receptor recruitment of mTOR as a mechanism for perturbed cognition in schizophrenia.
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DOI：
10.1002/emmm.201201410
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发表时间：
2012-10
影响因子：
11.1
通讯作者：
Marin, Philippe
中科院分区：
文献类型：
--
作者：
Meffre, Julie;Chaumont-Dubel, Severine;la Cour, Clotilde Mannoury;Loiseau, Florence;Watson, David J. G.;Dekeyne, Anne;Seveno, Martial;Rivet, Jean-Michel;Gaven, Florence;Deleris, Paul;Herve, Denis;Fone, Kevin C. F.;Bockaert, Joel;Millan, Mark J.;Marin, Philippe
精神分裂症患者的认知缺陷严重影响生活质量，目前的抗精神病药物控制较差。虽然5-HT6受体阻断具有特殊的前景，但其控制认知的分子底物仍不清楚。利用蛋白质组学策略，我们发现5-HT6受体与哺乳动物雷帕霉素靶蛋白（mTOR）途径的几种蛋白质相互作用，包括mTOR。此外，5-HT6受体激活增加了啮齿动物前额叶皮层（PFC）的mTOR信号传导。mTOR抑制剂雷帕霉素将这一信号传导事件与认知障碍联系起来，可以防止5-HT6激动剂引起的社会认知和新物体识别缺陷。在两种精神分裂症发育模型中，特别是新生儿苯环利定治疗和断奶后隔离饲养，PFC中mTOR的活性增强，而雷帕霉素与5-HT6拮抗剂一样，逆转了这些认知缺陷。这些观察结果表明，前额叶5-HT6受体募集mTOR有助于精神分裂症患者的认知紊乱，为其治疗控制提供了新的前景。
Cognitive deficits in schizophrenia severely compromise quality of life and are poorly controlled by current antipsychotics. While 5-HT6 receptor blockade holds special promise, molecular substrates underlying their control of cognition remain unclear. Using a proteomic strategy, we show that 5-HT6 receptors physically interact with several proteins of the mammalian target of rapamycin (mTOR) pathway, including mTOR. Further, 5-HT6 receptor activation increased mTOR signalling in rodent prefrontal cortex (PFC). Linking this signalling event to cognitive impairment, the mTOR inhibitor rapamycin prevented deficits in social cognition and novel object discrimination induced by 5-HT6 agonists. In two developmental models of schizophrenia, specifically neonatal phencyclidine treatment and post-weaning isolation rearing, the activity of mTOR was enhanced in the PFC, and rapamycin, like 5-HT6 antagonists, reversed these cognitive deficits. These observations suggest that recruitment of mTOR by prefrontal 5-HT6 receptors contributes to the perturbed cognition in schizophrenia, offering new vistas for its therapeutic control.
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