The Florey Institute of Neuroscience and Mental Health, Parkville, Melbourne, Victoria, Australia.
Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia.
J Neurochem. 2024 Sep;168(9):2285-2302. doi: 10.1111/jnc.16187. Epub 2024 Aug 2.
Attention deficits are frequently reported within the clinical autism population. Despite not being a core diagnostic feature, some aetiological theories place atypical attention at the centre of autism development. Drugs used to treat attention dysfunction are therefore increasingly prescribed to autistic patients, though currently off-label with uncertain efficacy. We utilised a rodent-translated touchscreen test of sustained attention in mice carrying an autism-associated R451C mutation in the neuroligin-3 gene (Nlgn3). In doing so, we replicated their cautious but accurate response profile and probed it using two widely prescribed attention-modulating drugs: methylphenidate (MPH) and atomoxetine (ATO). In wild-type mice, acute administration of MPH (3 mg/kg) promoted impulsive responding at the expense of accuracy, while ATO (3 mg/kg) broadly reduced impulsive responding. These drug effects were absent in Nlgn3 mice, other than a small reduction in blank touches to the screen following ATO administration. The absence of drug effects in Nlgn3 mice likely arises from their altered behavioural baseline and underlying neurobiology, highlighting caveats to the use of classic attention-modulating drugs across disorders and autism subsets. It further suggests that altered dopaminergic and/or norepinephrinergic systems may drive behavioural differences in the Nlgn3 mouse model of autism, supporting further targeted investigation.
注意力缺陷在临床自闭症人群中经常被报道。尽管它不是一个核心诊断特征，但一些病因理论将非典型注意力置于自闭症发展的中心。因此，用于治疗注意力功能障碍的药物越来越多地被开给自闭症患者，尽管目前是超适应证用药，疗效不确定。我们利用一种啮齿动物转化的持续性注意力触摸屏测试，在携带神经连接蛋白-3 基因（Nlgn3）R451C 突变的自闭症相关小鼠中进行了测试。这样，我们复制了它们谨慎但准确的反应特征，并使用两种广泛使用的注意力调节药物进行了探测：哌醋甲酯（MPH）和阿托西汀（ATO）。在野生型小鼠中，急性给予 MPH（3mg/kg）以牺牲准确性为代价促进冲动反应，而 ATO（3mg/kg）广泛减少冲动反应。除了 ATO 给药后对屏幕的空白触摸略有减少外，Nlgn3 小鼠中没有这些药物作用。Nlgn3 小鼠中药物作用的缺失可能源于其改变的行为基线和潜在的神经生物学，这突出了在跨障碍和自闭症亚组中使用经典注意力调节药物的注意事项。它进一步表明，改变的多巴胺能和/或去甲肾上腺素能系统可能会导致自闭症 Nlgn3 小鼠模型中的行为差异，支持进一步的靶向研究。
