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

• Published in: Journal of neurochemistry 2024-09, Vol.168 (9), p.2285
• Main Authors: Dingwall, R, May, C, Letschert, J, Renoir, T, Hannan, A J, Burrows, E L
• Format: Article
• Language: English
• Subjects: Adrenergic Uptake Inhibitors - pharmacology; Animals; Atomoxetine Hydrochloride - pharmacology; Attention - drug effects; Autistic Disorder - drug therapy; Autistic Disorder - genetics; Cell Adhesion Molecules, Neuronal - genetics; Central Nervous System Stimulants - pharmacology; Disease Models, Animal; Female; Male; Membrane Proteins - genetics; Methylphenidate - pharmacology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Tissue Proteins - genetics
• ISSN: 0022-3042; 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 (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.