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 cases 1 – 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 vasopressin 4 – 6 , which regulate aspects of social behaviour in mammals 7 . 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. An autism-associated mutation in Nlgn3 results in impaired oxytocin signalling in dopaminergic neurons and altered social behavioural responses in mice, and treatment with an inhibitor of MAP kinase-interacting kinases rescues these phenotypes.

中文翻译：

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自闭症小鼠模型中催产素反应和社会行为的拯救

开发自闭症谱系障碍治疗方法的一个基本挑战是病情的异质性。一百多个基因突变赋予自闭症的高风险，每个单独的突变仅占病例的一小部分 1-3 。风险基因的子集可以分为功能相关的途径，最突出的是那些涉及突触蛋白、翻译调节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 4-6 上，它们调节哺乳动物社会行为的各个方面 7 。然而，尚不清楚遗传风险因素是否由于催产素信号的改变而使个体易患自闭症。在这里，我们报告突触粘附分子 Nlgn3 中的自闭症相关突变导致多巴胺能神经元中的催产素信号受损以及小鼠对社会新奇测试的行为反应改变。值得注意的是，Nlgn3 的缺失伴随着腹侧被盖区域翻译稳态的破坏。用一种新的、高度特异性的、脑渗透性的 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传导和社会新奇反应。因此，这项工作确定了遗传自闭症风险因素 Nlgn3、翻译调节和催产素信号传导之间的趋同。关注这些共同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，这将使基于机制的患者群体分层能够提高治疗干预的成功率。Nlgn3 中的自闭症相关突变导致多巴胺能神经元中的催产素信号受损并改变小鼠的社会行为反应，并且用 MAP 激酶相互作用激酶抑制剂治疗可以挽救这些表型。