Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
Pharmacol Biochem Behav. 2020 Aug;195:172955. doi: 10.1016/j.pbb.2020.172955. Epub 2020 May 29.
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 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 mouse social phenotype to environmental modulation. To address this, NL3 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 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 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，其特征是社交沟通障碍和存在限制和重复行为。一种在编码突触粘附蛋白 neuroligin-3（NL3）的基因中表达与自闭症相关的 R451C 突变的小鼠模型已经得到了广泛的描述，并且表现出与 ASD 中观察到的核心特征相关的改变行为。然而，NL3 小鼠在社会行为方面的受损仍然存在争议，因为在不同实验室的各种检测中存在不一致的发现。这种不一致可能是由于 NL3 小鼠的社会表型对环境调节的敏感性增加而合理地解释。为了解决这个问题，NL3 小鼠从 4 周龄开始在标准或丰富的环境中饲养，然后进行行为测试。丰富的饲养增强了所有小鼠在三箱社交互动测试中与陌生小鼠的直接互动，然而，与之前的报道相反，NL3 小鼠在三箱测试中没有表现出社交互动受损。环境丰富增强了所有小鼠的攻击行为，但并没有特异性地改变之前在 NL3 小鼠中描述的升高的攻击表型。丰富的特定基因型效应包括 WT 小鼠的焦虑样行为减少，以及 NL3 小鼠的运动活性水平降低。虽然在社交行为中没有观察到丰富的基因型特异性效应，但所有小鼠的社交互动和攻击行为的普遍增加表明，这些行为易受饲养条件的影响。表达 ASD 相关突变的小鼠模型在阐明核心特征发展的神经生物学方面具有很大的效用，因此，集中精力研究表现出稳健表型的模型至关重要。鉴于本研究中的发现，我们建议采用一些方法来提高 ASD 小鼠模型的可重复性和再现性。
