The ketone body β-hydroxybutyrate ameliorates neurodevelopmental deficits in the GABAergic system of <i>daf-18/PTEN Caenorhabditis elegans</i> mutants.

Abstract

A finely tuned balance between excitation and inhibition (E/I) is essential for proper brain function. Disruptions in the GABAergic system, which alter this equilibrium, are a common feature in various types of neurological disorders, including autism spectrum disorders (ASDs). Mutations in <i>Phosphatase and Tensin Homolog (PTEN)</i>, the main negative regulator of the phosphatidylinositol 3-phosphate kinase/Akt pathway, are strongly associated with ASD. However, it is unclear whether <i>PTEN</i> deficiencies can differentially affect inhibitory and excitatory signaling. Using the <i>Caenorhabditis elegans</i> neuromuscular system, where both excitatory (cholinergic) and inhibitory (GABAergic) inputs regulate muscle activity, we found that <i>daf-18</i>/<i>PTEN</i> mutations impact GABAergic (but not cholinergic) neurodevelopment and function. This selective impact results in a deficiency in inhibitory signaling. The defects observed in the GABAergic system in <i>daf-18/PTEN</i> mutants are due to reduced activity of DAF-16/FOXO during development. Ketogenic diets (KGDs) have proven effective for disorders associated with E/I imbalances. However, the mechanisms underlying their action remain largely elusive. We found that a diet enriched with the ketone body β-hydroxybutyrate during early development induces DAF-16/FOXO activity, therefore improving GABAergic neurodevelopment and function in <i>daf-18/PTEN</i> mutants. Our study provides valuable insights into the link between <i>PTEN</i> mutations and neurodevelopmental defects and delves into the mechanisms underlying the potential therapeutic effects of KGDs.