Exogenous ketone bodies ameliorate behavioral defects associated with DAF-18/PTEN mutations

Abstract

The phosphatidylinositol 3-kinase (PI3K) signaling pathway is a conserved signal transduction cascade involved in several processes, including neurodevelopment. The lipid phosphatase DAF-18/PTEN inhibits the PI3K signaling pathway to activate DAF 16/FOXO. Mutations in DAF-18/PTEN impair neurodevelopment from worms to mammals due to DAF-16/FOXO inactivation. In humans, for instance, mutations in PTEN are strongly associated with autism spectrum disorders. During the last few years, growing evidence supports low-carbohydrate high-fat ketogenic diets (KGD) as nutritional strategies for treating core behavioral symptoms of neurodevelopmental disorders. The mechanistic bases of these beneficial effects are not understood. The reduced availability of carbohydrates in KGD leads to ketone bodies (β-hydroxybutyrate (βHB) and acetoacetate) synthesis as an energy supplement to the brain. Recently, βHB has been reported to induce FOXO transcription factor in mammals. We found that exogenous βHB also induces DAF-16/FOXO translocation in C. elegans. The fact that FOXO activation is crucial for neurodevelopment throughout the animal kingdom, raises the exciting possibility that exogenous βHB could mitigate behavioral defects associated with neurodevelopmental disorders. We here found that daf-18 mutants exhibit an inefficient escape response upon mechanical stimulation. Strikingly, these defects are ameliorated when these mutant animals were exposed to βHB throughout development. This suggests that the ketone body βHB can reduce neurodevelopmental defects caused by daf-18 mutations. We are now focused on analyzing whether daf-18 mutations lead to neuronal morphology aberrations in the escape circuit, and whether βHB can reduce these defects. Moreover, we plan to recapitulate human pten mutations associated with neurodevelopmental disorders in C. elegans and analyze the effects of ketone bodies. We also plan to evaluate whether βHB can rescue phenotypes in other mutants with compromised neurodevelopment. Our experiments will contribute to understanding the molecular mechanisms underlying KGD effects on neurodevelopmental disorders and may constitute a first step in validating βHB as a novel pharmacological treatment for these pathologies.