Circadian Clock Dysfunction Exacerbate Autistic-Like Behaviour and Wnt/β-Catenin Signalling Dysregulation in ASD Mice and Treatment of Melatonin.

This animal study looked at how sleep and body clock problems might be connected to autism. Researchers found that mice with autism-like behaviours had disrupted body clocks and problems with important brain signalling pathways. When they gave these mice melatonin (a natural sleep hormone), it helped improve both their behaviour and brain function.

This preclinical study investigated the relationship between circadian clock dysfunction and autism-like behaviours in mouse models. Researchers used valproic acid (VPA) exposure to induce autism-like behaviours and found that these mice showed altered circadian protein expression and disrupted Wnt signalling pathways. Bmal1 knockout mice showed exacerbated behavioural changes and further impaired signalling. Melatonin treatment reversed Wnt pathway downregulation and improved behavioural deficits in VPA-exposed mice.

The study suggests that circadian dysregulation may contribute to ASD pathogenesis through Bmal1-mediated effects on Wnt/β-catenin signalling, positioning melatonin as a potential therapeutic intervention.

Findings support investigating melatonin for sleep disturbances in autism, which affect 50-80% of autistic children. Results suggest circadian interventions may have broader behavioural benefits beyond sleep improvement through Wnt signalling modulation.

Animal model study using VPA-induced autism may not fully represent human ASD. Sample size not reported. Unclear if findings translate to clinical populations. Limited to specific molecular pathways.

Between 50% and 80% of children diagnosed with Autism Spectrum Disorder (ASD) are estimated to experience sleep disturbances, highlighting the importance of exploring the role of the circadian clock in ASD development. Previous studies have identified a potential link between Bmal1 deficiency and ASD in mouse models. In this study, we first characterise the expression patterns of circadian proteins. Subsequent behavioural tests and western blot analyses revealed that mice exposed to valproic acid (VPA) displayed autistic-like behaviours, along with altered circadian protein expression and disruption in Wnt signalling protein levels.

Further studies showed that Bmal1 knockout exacerbates these behavioural changes and further impaired Wnt signalling and downstream protein expression in VPA-exposed mice. Notably, treatment with the circadian biomarker melatonin reversed Wnt downregulation and improved the behaviour deficit in VPA-exposed mice. The therapeutic effect of melatonin appears to be mediated by its regulation of the Wnt/β-catenin signalling pathway, which is linked to Bmal1-mediated circadian dysfunction. Together, our findings provide experimental evidence supporting the role of circadian dysregulation in ASD pathogenesis, highlight the therapeutic potential of melatonin in VPA-exposed mice, and suggest that Bmal1 may act as a co-activator in the Wnt-β-catenin signalling pathway.