Both genetic variations and nutritional deficiency are associated with autism spectrum disorders and other neurological disorders. However, it is less clear whether or how nutritional deficiency and genetic variations influence each other under pathogenic conditions. ‘‘Valosin-containing protein’’ (VCP, also known as p97) is associated with multiple neurological disorders and regulates dendritic spine formation by controlling endoplasmic reticulum formation and protein syn- thesis efficiency. Increased protein synthesis ameliorates the dendritic spine defects of Vcp-deficient neurons. Therefore, we investigated if Vcp-deficient mice are sensitive to nutritional conditions. Here, we show that social interaction and contextual memory of Vcp-deficient mice are indeed influenced by different dietary protein levels. Moreover, leucine supplementation ameliorates the behavioral deficits and dendritic spine density of Vcp-deficient mice, strengthening evidence for the role of protein synthesis in VCP function. Our study illustrates that genetic variation and nutrient factors cross-talk to influence neuronal and behavioral phenotypes.