Abnormal synaptic proteomes, impaired neural ensembles, and defective behaviors in autism mouse models are ameliorated by dietary intervention with nutrient mixtures

Autism spectrum disorders (ASD) are a group of heterogeneous, behaviorally defined neurodevelopmental conditions influenced by both genetic and environmental factors. Here, we show that nutrients—an important environmental factor—can modulate synaptic proteomes, reconfigure neural ensembles, and improve social behaviors in ASD mouse genetic models. We analyzed Tbr1 ^+/− mice, a well-established model of ASD, using proteomic approaches and in vivo calcium imaging. Synaptic and metabolic proteomes were found to be sensitive to Tbr1 haploinsufficiency. Our results also revealed that Tbr1 haploinsufficiency promotes hyperactivation and hyperconnectivity of basolateral amygdala (BLA) neurons, enhancing the activity correlation between individual neurons and their corresponding ensembles. Zinc, branched-chain amino acids (BCAA), and serine—all nutrients known to regulate synapse formation and activity—were then combined into supplement cocktails and administered to Tbr1 ^+/− mice. This treatment altered synaptic and metabolic proteomes and normalized the activity and connectivity of the BLA in Tbr1 ^+/− mice during social interactions. We further show that although a low dose of individual nutrients did not alter social behaviors, treatment with supplement cocktails 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. Moreover, the supplement cocktails also improved social behaviors in Nf1 ^+/− and Cttnbp2 ^+/M120I mice, two additional ASD mouse models. Thus, our findings reveal aberrant neural connectivity in the BLA of Tbr1 ^+/− mice and indicate that dietary supplementation with zinc, BCAA, and/or serine offers a safe and accessible approach to mitigate neural connectivity and social behaviors across multiple ASD models.