Attenuated responses to attention‐modulating drugs in the neuroligin‐3R451C mouse model of autism

• Published in: Journal of neurochemistry Vol. 168; no. 9; pp. 2285 - 2302
• Main Authors: Dingwall, R., May, C., Letschert, J., Renoir, T., Hannan, A. J., Burrows, E. L.
• Format: Journal Article
• Language: English
• Published: New York Blackwell Publishing Ltd 01.09.2024
• Subjects: atomoxetine; Attention; Autism; autism spectrum disorder; continuous performance task; Dopamine receptors; Drug development; Drugs; Methylphenidate; neuroligin‐3 mouse model; Neurosciences; Touch screens
• ISSN: 0022-3042; 1471-4159; 1471-4159
• DOI: 10.1111/jnc.16187

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 (Nlgn3R451C). 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 Nlgn3R451C mice, other than a small reduction in blank touches to the screen following ATO administration. The absence of drug effects in Nlgn3R451C 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 Nlgn3R451C mouse model of autism, supporting further targeted investigation. Atypical attention is widely reported in autism and may contribute to the development of core traits. We therefore probed the ability of classic attention‐modulating drugs to ameliorate a previously identified attention phenotype in the neuroligin‐3 R451C mouse model of autism (Nlgn3R451C). These drugs altered responding as expected in wild‐type mice, an effect largely unobserved in Nlgn3R451C mice. Limited effectiveness of standard attention drugs in Nlgn3R451C mice may support the development of novel attention modulators for autism.