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A low-dose nutritional supplement combining zinc, branched-chain amino acids (BCAAs), and serine has been found to produce additive effects in improving neurological and behavioral deficits across three different autism mouse models. The research team led by Distinguished Research Fellow Yi-Ping Hsueh at the Institute of Molecular Biology, Academia Sinica, has unveiled a safe and broadly effective strategy that may help counteract the neural and behavioral abnormalities caused by autism-linked genetic mutations.

Autism spectrum disorder (ASD) has a remarkably high prevalence—according to the latest U.S. statistics, one in every 31 children is diagnosed with ASD. However, developing effective treatments has proven extremely challenging, as hundreds of genes are implicated in autism, each with distinct molecular functions. The traditional “one gene–one therapy” approach is thus impractical for such a complex condition. Moreover, because ASD symptoms appear early in life, effective interventions must be safe, well-tolerated, and suitable for long-term use—even from childhood.

Autism is known to be closely associated with dysfunction of synapses, the contact points that transmit signals between neurons. Given that many autism-related mutations lead to decreased synaptic number and activity, enhancing synaptic function, therefore, could be a promising strategy to alleviate autism symptoms.

Zinc, BCAAs, and serine are essential nutrients that, through different mechanisms, are known to enhance synaptic activity. High-dose supplementation of each has previously been shown to improve specific autism-like symptoms in mice. To achieve broader effects while minimizing potential side effects from high doses, Dr. Hsueh’s team combined these three nutrients at substantially lower concentrations. Remarkably, this low-dose nutrient mixture showed additive benefits, improving social behavior deficits in three distinct genetic models of autism.

Further proteomic analyses revealed that the supplement mixture increased synaptic protein expression in the brains of autism model mice, suggesting a molecular mechanism underlying its effects. Using advanced in vivo calcium imaging, the team demonstrated that the supplement mixture also normalized neuronal activity and connectivity in the brain during social interactions. These results provide compelling evidence that the low-dose nutrient mixture can modulate neuronal circuit activity and connectivity in real time.

This study was recently published in PLOS Biology. The co–first authors are Dr. Tzyy-Nan Huang, Senior Research Scientist at the Institute of Molecular Biology, and Ming-Hui Lin, PhD student at the Taiwan International Graduate Program. Other contributors include Dr. Tsan-Ting Hsu, Senior Research Scientist, and Chen-Hsin (Albert) Yu, Assistant Research Specialist. The National Science and Technology Council Frontier Program and the Academia Sinica Investigator Project Grant supported the work.