Pharmacological rescue of Ras signaling, GluA1-dependent synaptic plasticity, and learning deficits in a fragile X model.
Pharmacological rescue of Ras signaling, GluA1-dependent synaptic plasticity, and learning deficits in a fragile X model.
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DOI：
10.1101/gad.232470.113
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发表时间：
2014-02-01
影响因子：
10.5
通讯作者：
Zhu JJ
中科院分区：
文献类型：
--
作者：
Lim CS;Hoang ET;Viar KE;Stornetta RL;Scott MM;Zhu JJ
脆性X综合征是遗传性智力低下的最常见形式，由Fmr1基因功能丧失引起。Lim等人。发现激活5-羟色胺(5HT)2B亚型受体或多巴胺(DA)亚型1-样受体的化合物以及抑制5HT2A-Rs或D2-Rs的化合物可增强RAS信号、GluA1依赖的突触可塑性，以及在Fmr1基因敲除小鼠中的学习。低剂量联合5-羟色胺和多巴胺化合物可协同恢复正常学习。这表明，适当剂量和联合FDA批准的精神活性药物可能有效地治疗与脆性X综合征相关的认知障碍。脆性X综合征由Fmr1基因功能丧失引起，是遗传性智力低下最常见的形式，目前尚无有效的治疗方法。使用易于处理的动物模型，我们研究了几种FDA批准的精神活性药物的作用机制，这些药物对脆性X患者的认知表现有一定的改善作用。在这里，我们报道了激活5-羟色胺(5HT)2B亚型受体(5HT2b-Rs)或多巴胺(DA)亚型1-样受体(d1-Rs)和/或抑制5HT2a-Rs或D2-Rs的化合物适度增强Ras-PI3K/PKB信号输入、GluA1依赖的突触可塑性和Fmr1基因敲除小鼠的学习。出乎意料的是，这些5-羟色胺和DA化合物在低剂量下的组合协同刺激Ras-PI3K/PKB信号转导和依赖GluA1的突触可塑性，并显著恢复Fmr1基因敲除小鼠的正常学习，而不会引起焦虑相关的副作用。这些发现表明，适当剂量和联合FDA批准的精神活性药物可能有效地治疗与脆性X综合征相关的认知障碍。
Fragile X syndrome, caused by the loss of Fmr1 gene function, is the most common form of inherited mental retardation. Lim et al. find that compounds activating serotonin (5HT) subtype 2B receptors or dopamine (DA) subtype 1-like receptors and those inhibiting 5HT2A-Rs or D2-Rs enhance Ras signaling, GluA1-dependent synaptic plasticity, and learning in Fmr1 knockout mice. Combining 5HT and DA compounds at low doses synergistically restored normal learning. This suggests that properly dosed and combined FDA-approved psychoactive drugs may effectively treat the cognitive impairment associated with fragile X syndrome. Fragile X syndrome, caused by the loss of Fmr1 gene function, is the most common form of inherited mental retardation, with no effective treatment. Using a tractable animal model, we investigated mechanisms of action of a few FDA-approved psychoactive drugs that modestly benefit the cognitive performance in fragile X patients. Here we report that compounds activating serotonin (5HT) subtype 2B receptors (5HT2B-Rs) or dopamine (DA) subtype 1-like receptors (D1-Rs) and/or those inhibiting 5HT2A-Rs or D2-Rs moderately enhance Ras–PI3K/PKB signaling input, GluA1-dependent synaptic plasticity, and learning in Fmr1 knockout mice. Unexpectedly, combinations of these 5HT and DA compounds at low doses synergistically stimulate Ras–PI3K/PKB signal transduction and GluA1-dependent synaptic plasticity and remarkably restore normal learning in Fmr1 knockout mice without causing anxiety-related side effects. These findings suggest that properly dosed and combined FDA-approved psychoactive drugs may effectively treat the cognitive impairment associated with fragile X syndrome.
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影响因子：
7.7
作者：
Alejandra Rosales-Reynoso, Monica;Berenice Ochoa-Hernandez, Alejandra;Barros-Nunez, Patricio
通讯作者：
Barros-Nunez, Patricio
影响因子：
5.6
作者：
David, Denis J.;Wang, Jingwen;Hen, Rene
通讯作者：
Hen, Rene
DOI：
10.1523/jneurosci.0402-10.2010
发表时间：
2010-08-11
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Gross C;Nakamoto M;Yao X;Chan CB;Yim SY;Ye K;Warren ST;Bassell GJ
通讯作者：
Bassell GJ
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
25
作者：
Chen, X;Garelick, MG;Storm, DR
通讯作者：
Storm, DR