The Ketone Body β-hydroxybutyrate ameliorates neurodevelopmental deficits in the GABAergic system of daf-18/PTEN Caenorhabditis elegans mutants

Abstract

An increased Excitation/Inhibition (E/I) ratio in the brain is a hallmark of neurological disorders such as Autism Spectrum Disorder (ASD). Mutations in PTEN, a gene that encodes for the main negative regulator of the conserved PI3K/AKT pathway, are strongly associated with ASD. However, it is unclear how PTEN deficiencies can lead to E/I disequilibrium. The C. elegans neuromuscular system, where both excitatory (Cholinergic) and inhibitory (GABAergic) motor neurons regulate muscle activity, provides a proven simple model for studying E/I balance. We found that mutants in daf-18 (ortholog for PTEN) exhibit phenotypes typical of animals with deficient GABAergic signaling. While cholinergic neuron morphology is normal, we observed defects that occur specifically in GABAergic neurites. This selective impairment accounts for the disruption of the E/I balance in daf-18 mutants. In addition, we showed that the low activity of the transcription factor DAF-16 (ortholog for FOXO3A) during GABAergic neurodevelopment arises for the behavioral defects in daf-18 mutants. Ketogenic Diets (KGDs), in which the production of ketone bodies (KBs) is forced, have been established as an effective treatment for disorders associated with E/I imbalances. The mechanisms underlying its effect are not understood. We found that exposure to the KB hydroxybutyrate (βHB) during early development improves GABAergic neurodevelopment in daf-18 mutants. This effect depends on DAF-16/FOXO. Since the PI3K/ AKT pathway is highly conserved, this study may provide universal information on the proven link between PTEN mutations and neurodevelopmental defects and, equally important, the mechanisms underlying KGDs positive effects on neuronal disorders characterized by E/I imbalance.