Chronic administration of AFQ056/Mavoglurant restores social behaviour in Fmr1 knockout mice
Chronic administration of AFQ056/Mavoglurant restores social behaviour in Fmr1 knockout mice
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DOI：
10.1016/j.bbr.2012.10.059
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发表时间：
2013-02-15
影响因子：
2.7
通讯作者：
Willemsen, Rob
中科院分区：
文献类型：
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作者：
Gantois, Ilse;Pop, Andreea S.;Willemsen, Rob
脆性X综合征是由缺乏FMR 1蛋白（FMRP）引起的，导致严重的症状，包括智力残疾，多动和自闭症样行为。FMRP是一种RNA结合蛋白，在突触处刺激代谢型谷氨酸受体5（mGluR 5）后参与调节特异性靶mRNA的翻译。FMRP的缺失导致mGluR 5信号转导途径的活性增强。许多相互矛盾的结果已被报道有关Fmr 1基因敲除小鼠的社会行为缺陷，并鲜为人知的是参与mGluR 5途径对社会behavior.In这项研究中，一个三室任务被用来确定社会性和偏好的Fmr 1基因敲除小鼠的社会新奇。Fmr 1功能的破坏导致在社交过程中与陌生小鼠的互动增强，而在社交新奇试验的偏好过程中没有观察到显着变化。长期给予特异性mGluR 5拮抗剂AFQ 056/Mavoglurant能够将Fmr 1基因敲除小鼠的社交行为恢复到野生型同窝小鼠的水平，这些结果支持了mGluR 5信号通路对社交行为的重要性，并且AFQ 056/Mavoglurant可能作为潜在的治疗干预来挽救脆性X表型的各种行为方面。(c)2012爱思唯尔有限公司版权所有。
Fragile X syndrome is caused by lack of FMR1 protein (FMRP) leading to severe symptoms, including intellectual disability, hyperactivity and autistic-like behaviour. FMRP is an RNA binding protein involved in the regulation of translation of specific target mRNAs upon stimulation of metabotropic glutamate receptor 5 (mGluR5) at the synapse. The absence of FMRP leads to enhanced activity of mGluR5 signal transduction pathways. Many conflicting results have been reported regarding social behaviour deficits in Fmr1 knockout mice, and little is known about the involvement of mGluR5 pathways on social behaviour.In this study, a three-chambered task was used to determine sociability and preference for social novelty in Fmr1 knockout mice. Disruption of Fmr1 functioning resulted in enhanced interaction with stranger mouse during sociability while no significant changes were observed during preference for social novelty assay. Chronic administration of a specific mGluR5 antagonist, AFQ056/Mavoglurant, was able to restore sociability behaviour of Fmr1 knockout mice to levels of wild type littermates.These results support the importance of mGluR5 signalling pathways on social interaction behaviour and that AFQ056/Mavoglurant might be useful as potential therapeutic intervention to rescue various behavioural aspects of the fragile X phenotype. (c) 2012 Elsevier B.V. All rights reserved.