Multiple roles for mammalian target of rapamycin signaling in both glutamatergic and GABAergic synaptic transmission.
Multiple roles for mammalian target of rapamycin signaling in both glutamatergic and GABAergic synaptic transmission.
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DOI：
10.1523/jneurosci.1283-12.2012
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发表时间：
2012-08-15
期刊：
影响因子：
--
通讯作者：
Swann JW
中科院分区：
文献类型：
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作者：
Weston MC;Chen H;Swann JW
哺乳动物雷帕霉素靶蛋白（mTOR）信号通路整合多种细胞外信号以产生适当的翻译反应。在人类和小鼠模型中，mTOR信号传导在以癫痫、自闭症和认知障碍为特征的神经系统综合征中过度活跃。此外，雷帕霉素，一种临床上重要的免疫抑制剂，是mTOR信号传导的特异性和有效的抑制剂。虽然已知mTOR调节突触能神经元的生长和突触可塑性，但其对突触传递的基本参数的影响研究较少，并且其在调节GABA能传递中的作用尚未探索。因此，我们对雷帕霉素能和GABA能神经元进行了电生理学和形态学比较，其中mTOR信号要么因阻遏物Pten的丢失而增加，要么因雷帕霉素治疗而减少。我们发现，过度活跃的mTOR信号增加了诱发的突触反应在两个谷氨酸能和GABA能神经元约50%，由于可用于释放的突触囊泡的数量增加，形成的突触的数量和微型事件的大小。延长（72小时）雷帕霉素治疗防止这些异常，也减少了野生型谷氨酸能神经元，但不是GABA能神经元的突触传递。进一步的分析表明，mTOR通路的过度激活也可能通过干扰囊泡融合而损害突触前功能。尽管存在这种突触前损伤，Pten丢失的净效应是增强GABA能和多巴胺能神经元的突触传递，这具有许多意义-取决于发育期间mTOR抑制基因在大脑中发生突变的位置。
The mammalian target of rapamycin (mTOR) signaling pathway in neurons integrates a variety of extracellular signals to produce appropriate translational responses. mTOR signaling is hyperactive in neurological syndromes in both humans and mouse models that are characterized by epilepsy, autism and cognitive disturbances. In addition, rapamycin, a clinically important immunosuppressant, is a specific and potent inhibitor of mTOR signaling. While mTOR is known to regulate growth and synaptic plasticity of glutamatergic neurons, its effects on basic parameters of synaptic transmission are less well studied, and its role in regulating GABAergic transmission is unexplored. We therefore performed an electrophysiological and morphological comparison of glutamatergic and GABAergic neurons in which mTOR signaling was either increased by loss of the repressor Pten or decreased by treatment with rapamycin. We found that hyperactive mTOR signaling increased evoked synaptic responses in both glutamatergic and GABAergic neurons by approximately 50%, due to an increase in the number of synaptic vesicles available for release, the number of synapses formed and the miniature event size. Prolonged (72 hours) rapamycin treatment prevented these abnormalities and also decreased synaptic transmission in wild-type glutamatergic, but not GABAergic, neurons. Further analyses suggested that hyperactivation of the mTOR pathway also impairs presynaptic function, possibly by interfering with vesicle fusion. Despite this presynaptic impairment, the net effect of Pten loss is enhanced synaptic transmission in both GABAergic and glutamatergic neurons, which has numerous implications – depending on where in the brain mutations of an mTOR suppressor gene takes place during development.