Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterised by impairments in social communication and the presence of restrictive and repetitive behaviours. A mouse model expressing an autism-associated R451C mutation in the gene encoding the synaptic adhesion protein neuroligin-3 (NL3) has been extensively characterised and shows altered behaviour relevant to core traits observed in ASD. Reported impairments in social behaviours in NL3^R451C mice however remain controversial due to inconsistent findings in various assays across different laboratories. Such inconsistencies could plausibly be explained by an increased susceptibility of the NL3^R451C mouse social phenotype to environmental modulation. To address this, NL3^R451C mice were housed in standard or enriched housing from 4 weeks of age prior to behavioural testing. Enrichment rearing enhanced direct interactions with the stranger mouse in all mice in the three-chamber social interaction test however, NL3^R451C mice did not show impairment in social interaction in the three-chamber test, in contrast with previous reports. Environmental enrichment enhanced aggressive behaviour in all mice, and did not specifically alter the heightened aggressive phenotype previously described in NL3^R451C mice. Specific genotype effects of enrichment included reduced anxiety-like behaviour in WT mice, and lower locomotor activity levels in NL3 mice. While genotype-specific effects of enrichment were not seen on social behaviour, the general increase in affiliative social interaction and aggression seen in all mice, indicates that these behaviours, are vulnerable to change based on housing condition. Mouse models expressing ASD-associated mutations have great utility in elucidating the neurobiology underling development of core traits and it is crucial that efforts are focussed on those models exhibiting robust phenotypes. In light of the findings in the present study, we suggest approaches to improve replicability and reproducibility in mouse models of ASD.

自闭症谱系障碍（ASD）是一种神经发育障碍，其特征在于社交沟通障碍以及限制性和重复性行为的存在。在编码突触粘附蛋白neuroligin-3（NL3）的基因中表达自闭症相关的R451C突变的小鼠模型已得到广泛表征，并显示出与ASD中观察到的核心性状相关的行为改变。NL3 ^R451C小鼠中社交行为的报告障碍仍然存在争议，因为在不同实验室进行的各种检测结果不一致。NL3 ^R451C小鼠社交表型对环境调节的敏感性增加，可以合理地解释这种不一致。为了解决这个问题，NL3 ^R451C在进行行为测试之前，将小鼠从4周龄起放入标准或丰富的住房中。在三室社交互动测试中，富集饲养增强了与所有陌生小鼠的直接互动，但是，与以前的报道相比，NL3 ^R451C小鼠在三室社交测试中并未显示出社交互动受损。环境富集增强了所有小鼠的攻击行为，并且没有特别改变先前在NL3 ^R451C中描述的升高的攻击表型老鼠。富集的特定基因型效应包括减少野生型小鼠的焦虑样行为，以及降低NL3小鼠的自发活动水平。虽然未见到基因型特异的富集对社交行为的影响，但在所有小鼠中都发现亲属社交互动和攻击性普遍增加，表明这些行为很容易根据居住条件而改变。表达ASD相关突变的小鼠模型在阐明支持核心性状发展的神经生物学方面具有很大的用途，至关重要的是，应将精力集中在表现出强大表型的模型上。根据本研究的发现，我们提出了改善ASD小鼠模型中可复制性和可再现性的方法。