Vocal communication in asocial BTBR mice is more malleable by a ketogenic diet in juveniles than adults

Abstract

Deficits in social communication and language development are a hallmark of autism spectrum disorder currently with no effective approaches to reduce the negative impact. Interventional studies using animal models have been very limited in demonstrating improved vocal communication. Autism has been proposed to involve metabolic dysregulation. Ketogenic diet (KD) is a metabolism-based therapy for medically intractable epilepsy, and its applications in other neurological conditions have been increasingly tested. However, how KD would affect vocal communication has not been explored. The BTBR mouse strain is widely used to model asocial phenotypes. They display robust and pronounced deficits in vocalization during social interaction, and have metabolic changes implicated in autism.We investigated the effects of KD on ultrasonic vocalizations (USVs) in juvenile and adult BTBR mice during male–female social encounters.After a brief treatment with KD, the number, spectral bandwidth, and much of the temporal structure of USVs were robustly closer to control levels in both juvenile and adult BTBR mice. Composition of call categories and transitioning between individual call subtypes were more effectively altered to more closely align with the control group in juvenile BTBR mice.Together, our data provide further support to the hypothesis that metabolism-based dietary intervention could modify disease expression, including core symptoms, in autism. Future studies should tease apart the molecular mechanisms of KD’s effects on vocalization.