The ketone body β-hydroxybutyrate ameliorates neurodevelopmental deficits in the GABAergic system ofdaf-18/PTEN Caenorhabditis elegansmutants

Abstract

Increased Excitation/Inhibition (E/I) ratio in the brain is a hallmark of neurological disorders, such as Autism Spectrum Disorders (ASD). Mutations in PTEN, the main PI3K/Akt pathway negative regulator, are strongly associated with ASD. It is unclear how PTEN deficiencies lead to E/I disequilibrium. Using C. elegans neuromuscular system as a model for studying E/I balance, we find that daf-18/PTEN mutations affect GABAergic (but not cholinergic) neurodevelopment, leading to behavioral phenotypes typical of an increased E/I ratio. The specific defects in GABAergic development in daf-18 mutants are due to the reduced activity of DAF-16/FOXO3A. Ketogenic diets (KGDs) are effective approaches for disorders associated with E/I imbalances. However, their mechanisms of action are not understood. We show, in daf-18 mutants, that a diet enriched with the ketone body hydroxybutyrate during early development improves GABAergic neurodevelopment and rescued behavioral defects in a DAF-16/FOXO-dependent manner. Our study offers universal insights into the proven link between PTEN mutations and neurodevelopmental defects and provides new insights into the mechanisms underlying KGDs' positive effects on neuronal disorders characterized by E/I imbalance.