NMDA receptor activation regulates sociability by its effect on mTOR signaling activity.
NMDA receptor activation regulates sociability by its effect on mTOR signaling activity.
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DOI：
10.1016/j.pnpbp.2015.02.009
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发表时间：
2015-07-03
影响因子：
5.6
通讯作者：
Deutsch SI
中科院分区：
文献类型：
--
作者：
Burket JA;Benson AD;Tang AH;Deutsch SI
结节性硬化症复合体是自闭症谱系障碍的一种综合征形式，与神经元(例如小脑浦肯野细胞)中mTORCL的失控活动有关。MTORCL是一种具有丝氨酸/苏氨酸激酶活性的复杂蛋白，是细胞表面通过神经递质(如谷氨酸和乙酰胆碱)和神经生长因子(如脑源性神经营养因子)转导的信号级联反应中的关键下游分子。有趣的是，结节性硬化症患者智力障碍的严重程度可能更多地与代谢紊乱(即mTOR信号过度活跃)有关，而不是皮质结节的密度。最近的几篇报道表明，mTORCL的抑制剂雷帕霉素可以改善结节性硬化症和自闭症谱系障碍小鼠的社交等症状，这与mTORCL过度活性发挥着重要的致病作用相一致。NMDA受体的激活也可能通过至少两种可能的机制抑制mTORCL的活性：调节神经元内精氨酸的积累和特定的细胞外信号调节激酶(即ERK1/2)的磷酸化状态，这两种机制都是mTORCL活性的“驱动力”。可以想象，在自闭症谱系障碍的小鼠模型中，用激动剂靶向NMDA受体的亲社会效应是由于它们能够抑制神经元中的mTORC1活动。在慢性神经发育障碍，如自闭症谱系障碍中，通过激活NMDA受体来抑制mTORC1过度活性的策略可能比直接抑制它更受欢迎。
Tuberous Sclerosis Complex is one example of a syndromic form of autism spectrum disorder associated with disinhibited activity of mTORCl in neurons (e.g., cerebellar Purkinje cells). mTORCl is a complex protein possessing serine/threonine kinase activity and a key downstream molecule in a signaling cascade beginning at the cell surface with the transduction of neurotransmitters (e.g., glutamate and acetylcholine) and nerve growth factors (e.g., Brain-Derived Neurotrophic Factor). Interestingly, the severity of the intellectual disability in Tuberous Sclerosis Complex may relate more to this metabolic disturbance (i.e., overactivity of mTOR signaling) than the density of cortical tubers. Several recent reports showed that rapamycin, an inhibitor of mTORCl, improved sociability and other symptoms in mouse models of Tuberous Sclerosis Complex and autism spectrum disorder, consistent with mTORCl overactivity playing an important pathogenic role. NMDA receptor activation may also dampen mTORCl activity by at least two possible mechanisms: regulating intraneuronal accumulation of arginine and the phosphorylation status of a specific extracellular signal regulating kinase (i.e., ERK1/2), both of which are “drivers” of mTORCl activity. Conceivably, the prosocial effects of targeting the NMDA receptor with agonists in mouse models of autism spectrum disorders result from their ability to dampen mTORC1 activity in neurons. Strategies for dampening mTORC1 overactivity by NMDA receptor activation may be preferred to its direct inhibition in chronic neurodevelopmental disorders, such as autism spectrum disorders.
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影响因子：
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作者：
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