Exogenous Ketone Bodies Modulation Of Gabaergic Signaling In C. elegans

Abstract

Mutations in PTEN (a negative regulator of the PI3K pathway) are associated with neurodevelopmental disorders, epilepsy, and schizophrenia. Several reports suggest that an increase in the ex- citation/inhibition (E/I) ratio in the brain is a hallmark of these disor- ders. The C. elegans Neuro-Muscular system, where both excitatory (ACh) and inhibitory (GABA) neurons innervate muscles, provides a suitable model for studying E/I balance. Combining pharmacologi- cal and behavior assays, we found that daf-18 (C. elegans ortholog for PTEN) mutants are hypersensitive to cholinergic drugs, suggest- ing a deficit in GABAergic signaling. 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 criti- cal role. Moreover, using microscopy techniques, we observed that daf-18 mutants exhibit morphological defects in GABAergic neurons (abnormal branching, and incomplete commissures). In contrast, we did not find significant differences in the morphology of cholinergic 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, we found that the GABAergic deficit in daf-18 mutants is entirely dependent on the inactivation of the transcription factor DAF-16/FOXO. Ketogenic Diets have been used for refractory epilepsy. The mechanisms un- derlying this therapeutic effect remain elusive. We found that expo- sure to the ketone body hydroxybutyrate (βHB) during early devel- opment 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 E/I imbalances in mammals.