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科学家在自闭症小鼠模型中实现社交行为恢复
2020-08-08 13:26
来源：小柯机器人

瑞士巴塞尔大学Peter Scheiffele小组在自闭症小鼠模型中实现催产素反应和社交行为的恢复。这一研究成果于2020年8月5日在线发表在《自然》上。

研究人员发现，突触粘附分子Nlgn3中的自闭症相关突变会导致多巴胺能神经元的催产素信号转导受损，并改变小鼠对社交新鲜感测试的行为反应。值得注意的是，Nlgn3的丧失伴随着腹侧被盖区翻译稳态的破坏。用一种新的、高度特异性的脑渗透性MAP激酶相互作用激酶抑制剂治疗Nlgn3基因敲除小鼠，可重置mRNA的翻译并恢复催产素信号转导和社交新鲜感反应。
 
因此，这项工作确定了遗传自闭症危险因素Nlgn3、翻译调节和催产素信号之间的关联。专注于这种常见的核心可塑性元素可能会提供一种实用的方法来克服自闭症的异质性。最终，这可能实现患者群体的分层，从而增加治疗干预的成功率。
 
据了解，治疗自闭症谱系障碍的根本挑战在于病情的异质性。一百多个基因突变涉及自闭症高风险，而每个个体突变仅占病例的一小部分。风险基因亚群可以分为功能相关的途径，最主要是涉及突触蛋白、翻译调控和染色质修饰的途径。为了尽量减少这种遗传复杂性，最近的治疗策略集中在神经肽催产素和加压素，它们参与调节哺乳动物的社会行为。然而，目前尚不清楚遗传风险因素是否因催产素信号转导而使个体容易产生自闭。
 
附：英文原文

Title: Rescue of oxytocin response and social behaviour in a mouse model of autism

Author: Hanna Hrnberg, Enrique Prez-Garci, Dietmar Schreiner, Laetitia Hatstatt-Burkl, Fulvio Magara, Stephane Baudouin, Alex Matter, Kassoum Nacro, Eline Pecho-Vrieseling, Peter Scheiffele

Issue&Volume: 2020-08-05

Abstract: A fundamental challenge in developing treatments for autism spectrum disorders is the heterogeneity of the condition. More than one hundred genetic mutations confer high risk for autism, with each individual mutation accounting for only a small fraction of cases1,2,3. Subsets of risk genes can be grouped into functionally related pathways, most prominently those involving synaptic proteins, translational regulation, and chromatin modifications. To attempt to minimize this genetic complexity, recent therapeutic strategies have focused on the neuropeptides oxytocin and vasopressin4,5,6, which regulate aspects of social behaviour in mammals7. However, it is unclear whether genetic risk factors predispose individuals to autism as a result of modifications to oxytocinergic signalling. Here we report that an autism-associated mutation in the synaptic adhesion molecule Nlgn3 results in impaired oxytocin signalling in dopaminergic neurons and in altered behavioural responses to social novelty tests in mice. Notably, loss of Nlgn3 is accompanied by a disruption of translation homeostasis in the ventral tegmental area. Treatment of Nlgn3-knockout mice with a new, highly specific, brain-penetrant inhibitor of MAP kinase-interacting kinases resets the translation of mRNA and restores oxytocin signalling and social novelty responses. Thus, this work identifies a convergence between the genetic autism risk factor Nlgn3, regulation of translation, and oxytocinergic signalling. Focusing on such common core plasticity elements might provide a pragmatic approach to overcoming the heterogeneity of autism. Ultimately, this would enable mechanism-based stratification of patient populations to increase the success of therapeutic interventions.

DOI: 10.1038/s41586-020-2563-7

Source: https://www.nature.com/articles/s41586-020-2563-7

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html


本期文章：《自然》：Online/在线发表

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