Ketogenic modulation of gabaergic signalig in C. elegans

Abstract

TEN is a negative regulator of the PI3K pathway. Mutations in this gene are associated with neurodevelopmental disorders, epilepsy, and schizophrenia. Several reports suggest that an increase in the excitation/inhibition ratio in the brain is a hallmark of these disorders. The C. elegans NM system, where both excitatory (ACh) and inhibitory (GABA) neurons innervate muscles, provides a suitable model for studying E/I balance. We found that daf-18 (C. elegans ortholog for PTEN) mutants are hypersensitive to cholinergic drugs, suggesting a deficit in GABAergic signaling. Moreover, daf-18 mutants are deficient in eliciting complex movements such as the “omega turn”, a sharp turn in which the GABAergic inhibition on dorsal muscles plays a critical role. We also found that daf-18 mutants exhibit morphological defects in GABAergic neurons. DAF-18 specific rescue in GABAergic neurons partially rescued the defective phenotypes, suggesting an autonomic role of the PI3K pathway in GABAergic function. In addition, our genetic experiments demonstrated that the GABAergic deficit in daf-18 mutants is entirely dependent on the inactivation of the transcription factor DAF-16/FOXO. Ketogenic Diets (KDs) have been used since the 1920s for epilepsy who were refractory to GABAergic medications. The mechanisms underlying this therapeutic effect are not understood. We found that exposure to the ketone body hydroxybutyrate (βHB) during early development ameliorated GABA defects in daf-18 mutants. Interestingly, this ketone body does not alleviate the defects observed in daf-16/FOXO mutants, suggesting an essential role of this transcription factor in the βHB effect. Since fundamental processes are highly conserved throughout the animal kingdom, this study may contribute to the understanding of disorders associated with imbalances between excitatory and inhibitory signals in mammals