Autistic-Like Syndrome in Mu Opioid Receptor Null Mice is Relieved by Facilitated mGluR4 Activity
Autistic-Like Syndrome in Mu Opioid Receptor Null Mice is Relieved by Facilitated mGluR4 Activity
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DOI：
10.1038/npp.2014.59
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发表时间：
2014-08-01
影响因子：
7.6
通讯作者：
Kieffer, Brigitte L.
中科院分区：
文献类型：
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作者：
Becker, Jerome A. J.;Clesse, Daniel;Kieffer, Brigitte L.
自闭症谱系障碍（ASD）的病因在很大程度上仍然未知。确定自闭症的脆弱性基因是该领域的一个重大挑战，并允许开发用于转化研究的动物模型。缺乏μ阿片受体基因（Oprm 1（-/-））的小鼠最近被提出作为自闭症的单基因小鼠模型，基于社会行为和沟通技能的严重缺陷。我们证实了这一假设，表明成年Oprm 1（-/-）动物重演自闭症的核心和多种共病行为症状，并显示该疾病的解剖，神经化学和遗传标志。慢性促进mGluR 4信号传导，我们确定为一种新的药理学目标，在这些小鼠的ASD，是更有效地缓解行为缺陷比参考分子利培酮。总而言之，我们的数据提供了第一个证据，即破坏μ阿片受体信号传导足以引发全面的自闭症综合征，可能是通过钝化的社会奖励过程，这种小鼠模型为治疗创新开辟了有希望的途径。
The etiology of Autism Spectrum Disorders (ASDs) remains largely unknown. Identifying vulnerability genes for autism represents a major challenge in the field and allows the development of animal models for translational research. Mice lacking the mu opioid receptor gene (Oprm1(-/-)) were recently proposed as a monogenic mouse model of autism, based on severe deficits in social behavior and communication skills. We confirm this hypothesis by showing that adult Oprm1(-/-) animals recapitulate core and multiple comorbid behavioral symptoms of autism and also display anatomical, neurochemical, and genetic landmarks of the disease. Chronic facilitation of mGluR4 signaling, which we identified as a novel pharmacological target in ASDs in these mice, was more efficient in alleviating behavioral deficits than the reference molecule risperidone. Altogether, our data provide first evidence that disrupted mu opioid receptor signaling is sufficient to trigger a comprehensive autistic syndrome, maybe through blunted social reward processes, and this mouse model opens promising avenues for therapeutic innovation.