School of Biological Sciences, Highfield Campus, University of Southampton, Southampton SO17 1BJ, UK.
Hum Mol Genet. 2021 Jan 6;29(21):3546-3553. doi: 10.1093/hmg/ddaa232.
Autism spectrum disorder (ASD) is characterized by a triad of behavioural impairments including social behaviour. Neuroligin, a trans-synaptic adhesion molecule, has emerged as a penetrant genetic determinant of behavioural traits that signature the neuroatypical behaviours of autism. However, the function of neuroligin in social circuitry and the impact of genetic variation to this gene is not fully understood. Indeed, in animal studies designed to model autism, there remains controversy regarding the role of neuroligin dysfunction in the expression of disrupted social behaviours. The model organism, Caenorhabditis elegans, offers an informative experimental platform to investigate the impact of genetic variants on social behaviour. In a number of paradigms, it has been shown that inter-organismal communication by chemical cues regulates C. elegans social behaviour. We utilize this social behaviour to investigate the effect of autism-associated genetic variants within the social domain of the research domain criteria. We have identified neuroligin as an important regulator of social behaviour and segregate the importance of this gene to the recognition and/or processing of social cues. We also use CRISPR/Cas9 to edit an R-C mutation that mimics a highly penetrant human mutation associated with autism. C. elegans carrying this mutation phenocopy the behavioural dysfunction of a C. elegans neuroligin null mutant, thus confirming its significance in the regulation of animal social biology. This highlights that quantitative behaviour and precision genetic intervention can be used to manipulate discrete social circuits of the worm to provide further insight into complex social behaviour.
自闭症谱系障碍（ASD）的特征是行为障碍三联征，包括社交行为。神经黏连蛋白是一种跨突触黏附分子，它已成为行为特征的主要遗传决定因素，这些行为特征标志着自闭症的神经异常行为。然而，神经黏连蛋白在社交回路中的功能以及该基因的遗传变异的影响尚未完全了解。事实上，在旨在模拟自闭症的动物研究中，神经黏连蛋白功能障碍在破坏社交行为表达中的作用仍然存在争议。模式生物秀丽隐杆线虫为研究遗传变异对社交行为的影响提供了一个信息丰富的实验平台。在许多范式中，已经表明通过化学线索进行的生物体间通讯调节秀丽隐杆线虫的社交行为。我们利用这种社交行为来研究自闭症相关遗传变异在研究领域标准的社交领域中的影响。我们已经确定神经黏连蛋白是社交行为的重要调节因子，并将该基因的重要性分离为对社交线索的识别和/或处理。我们还使用 CRISPR/Cas9 编辑模仿与自闭症相关的高度穿透性人类突变的 R-C 突变。携带这种突变的秀丽隐杆线虫模拟了秀丽隐杆线虫神经黏连蛋白缺失突变体的行为功能障碍，从而证实了它在调节动物社交生物学中的重要性。这突出表明，定量行为和精确遗传干预可以用于操纵蠕虫的离散社交回路，以进一步深入了解复杂的社交行为。
