Autism-Linked Behaviors in Mice Reduced by Nutrient Trio

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Studies led by a team at Academia Sinica in Taiwan have found that a low-dose mixture of zinc, serine, and branch-chain amino acids (BCAAs) can alleviate behavioral deficits in three different mouse models of autism spectrum disorder (ASD). The study, reported in PLoS Biology by Tzyy-Nan Huang, PhD, and Ming-Hui Lin, PhD, and colleagues, found that when combined together, these three dietary supplements promoted communication between neurons in the brain and improve social behaviors.

Research co-lead Yi-Ping Hsueh, PhD, summarized, “As hundreds of genes are implicated in autism, each with distinct molecular functions, a ‘one gene–one therapy’ approach is impractical for addressing the complexity of ASD. Our findings show that a low-dose nutrient mixture containing zinc, branched-chain amino acids (BCAAs), and serine—working synergistically to improve synaptic function and social behaviors across three ASD mouse models—offers a safer and more practical strategy for long-term, broad application, even beginning in childhood.”

Corresponding author Hsueh and colleagues described their findings in a paper titled “Low-dose mixtures of dietary nutrients ameliorate behavioral deficits in multiple mouse models of autism,” in which they concluded, “Together, our study provides evidence for potential therapeutic treatments of ASD-linked deficiencies using dietary supplementation with multiple nutrients.”

Autism spectrum disorder (ASD) is a group of neurodevelopmental conditions that are characterized by two core behavioral symptoms, the authors wrote, those being impairments in social behavior and communication, and the presence of restricted, repetitive behaviors and sensory abnormalities. Autism spectrum disorder is known to result from abnormal neural development that affects how neurons are connected.

“ASD arises from a combination of genetic and environmental factors that influence neural development—particularly synapse formation and signaling—ultimately leading to impaired neural connectivity,” the team explained. “The crosstalk between genetic variations and environmental factors and the outcomes for synaptic functions and neural ensembles are critical issues in ASD research, yet many aspects of this topic remain to be investigated.”

Nutrition is known to be one of the environmental factors that influences ASD. “Accord­ingly, dietary interventions have been proposed as a treatment avenue,” the team suggested. Individually, zinc, serine, and branch-chain amino acids are all thought to have positive effects on neural connectivity. “Dietary supplementation with these nutrients may improve synapse formation and maintenance, as well as promote synaptic responses, to ameliorate neuronal function,” the investigators continued. They hypothesized that a mixture of the three would be a more effective treatment than any individually and that the necessary dosages of each could be lowered. They tested their theory in three mouse models of ASD, Tbr1^+/− mice, Nf1^+/− mice, and and Cttnbp2^+/M120I mice.

The team designed their investigation in three stages. First, proteomic analysis was performed to investigate altered protein expression in the brain. Second, they used in vivo calcium imaging to dissect the neural ensembles of the basolateral amygdala (BLA). They then carried out behavioral assays to monitor the beneficial effects of dietary supplementation on the social behaviors of Tbr1^+/− mice. They found that the cocktail of serine, zinc and BCAAs altered the animals’ brains so that the expression of proteins in the synapse resembled those of normal mice. The team showed that the abnormal hyperactivity of neurons in the amygdala was reduced after taking the cocktail. “Overall, the results of our suite of in vivo calcium imaging analyses indicate that Tbr1 deficiency results in hyperactivity and hyperconnectivity of BLA neurons during social interaction, consequently modulating BLA neuronal ensembles,” they wrote. “Treatment with our supplement cocktail corrects the abnormal neuronal activity and connectivity of the BLA in Tbr1^+/− mice.”

Behavioral studies demonstrated that social behaviors in the animals improved after they were given the cocktail. In contrast, when each supplement was given separately, the same dosages had no effect on behavior. “We further show that although a low dose of individual nutrients did not alter social behaviors, treatment with supplement mixtures containing low-dose individual nutrients improved social behaviors and associative memory of Tbr1^+/- mice, implying a synergistic effect of combining low-dose zinc, BCAA, and serine,” the team stated.

The supplemental cocktails also improved social behaviors in two additional mouse models of autism, Nf1^+/− mice, and and Cttnbp2^+/M120I mice, demonstrating that it’s the synergistic effect of combining the three supplements that allows it to be effective at low doses.

“Through a combination of proteomic analysis, in vivo calcium imaging, and behavioral assays, we have demonstrated that supplementation with cocktails containing low doses of multiple nutrients can restore protein expression profiles and neural connectivity in the brains of multiple ASD mouse models, thereby improving their social behaviors,” the team concluded. “These findings have revealed a promising new avenue for dietary therapy in the treatment of ASD.”

Tzyy-Nan Huang, one of the study’s first authors, emphasized, “High doses of individual nutrient supplements such as zinc, branched-chain amino acids, and serine can improve synaptic function through different mechanisms, but low doses of any single nutrient alone are ineffective. It is exciting to see that combining these nutrients at low doses successfully restores synaptic proteomes and enhances social behaviors in three different mouse models of autism.”

Ming-Hui Lin, the study’s co–first author, added, “I was thrilled to observe that just seven days of treatment with the nutrient mixture significantly modulated neuronal circuit activity and connectivity in real time. These results provide strong support for the beneficial effects of low-dose nutrient supplement combinations.”