A combination of three nutrients improves social and neural traits in mouse models of autism

Neurodevelopmental disorders, such as autism and intellectual disability, can be caused by multiple genetic and environmental factors. While their genetic causes have been extensively researched in recent years, much less is known about the various environmental factors involved in these neurological disorders. In the study published in the journal PLOS Biology, the authors use several mouse models of autism spectrum disorder (ASD) to demonstrate that supplementing the diet with various nutrients for just one week can improve the neurological symptoms of these mice, which is reflected in an improvement in their social behaviour and cognitive abilities (memory). In addition, the authors correlate these “behavioural improvements” in mice with the restoration of activity and connectivity in a specific brain region, the basolateral amygdala, which is involved in associative memory in situations of fear or pain. Thus, the combination of low doses of zinc (Zn), serine and other branched-chain amino acids (such as leucine, isoleucine and valine), but not when administered individually, has a beneficial effect in alleviating ASD-related social deficits in these mice. 

The authors draw on previous work to explain the mechanisms of action of these dietary supplements. Although they show through proteomics experiments that these nutrients increase the levels of certain synaptic proteins with important functions in neuronal communication, they do not demonstrate that ASD symptoms are caused by deficits in these proteins or nutrients. In my opinion, to better understand the molecular alterations involved, proteomic analysis and subsequent validation by immunoblot should have been performed in the affected areas of the brain (the basolateral amygdala) rather than in the entire brain, as this may have masked the data most relevant to the study. 

Although interesting and promising, these results should be treated with caution; epidemiological and clinical studies should be carried out to validate them in humans.

One comment on the press release: I would refrain from referring to ‘autistic mice’. Autism is a human condition, whereas the mouse models used in this study show selected genetic features and selected behavioural features relevant to autism, but clearly not the full spectrum of the condition. Researchers and journalists should be careful not to overstate the similarity between animal models and human conditions.

The evidence that the trio of nutritional supplements improves behavioural impairments in the mouse models is limited due to problems with the statistical analyses and with the design of the experiments. First, convincing statistical support for the claim that the behavioural impairments in the mice with genetic features linked to autism compared to control mice are smaller following treatment with the trio of supplements than following other treatments (individual supplements or water, which was used as control treatment) would require the demonstration of a significant statistical interaction between treatments and mouse genotype. However, except for the treatment effects on one test of social behaviour in one of the mouse models, this important statistical interaction was not demonstrated. This is an example of falsely claiming ‘differences between differences’ (i.e., different behavioural differences/impairments in different treatment groups) without the appropriate statistical support for such differences ―a relatively common error in neuroscience studies―.

Second, several of the experiments compared the impact of different treatments by testing social behaviour repeatedly within the same mice but following different treatments. The problem is that the control treatment (water) was always tested first, whereas the trio of supplement was tested last. So, any improvement observed with the trio of supplements could have reflected repeated testing, rather than the beneficial action of the trio of supplement.