KETOGENIC MODULATION OF GABAERGIC SIGNALING IN C. elegans

GIUNTI, S.; DE ROSA, M.J.; RAYES, D.

Taller; V Taller de Biología Celular y del Desarrollo; 2022

TEN is a neganve regulator of the PI3K pathway. Mutanons in this gene are associated withneurodevelopmental disorders, epilepsy, and schizophrenia. Several reports suggest that an increase inthe excitanon/inhibinon rano 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 suitablemodel for studying E/I balance. We found that daf-18 (C. elegans ortholog for PTEN) mutants arehypersensinve to cholinergic drugs, suggesnng a deficit in GABAergic signaling. Moreover, daf-18mutants are deficient in elicinng complex movements such as the ?omega turn?, a sharp turn in whichthe GABAergic inhibinon on dorsal muscles plays a crincal role. We also found that daf-18 mutantsexhibit morphological defects in GABAergic neurons. DAF-18 specific rescue in GABAergic neuronsparnally rescued the defecnve phenotypes, suggesnng an autonomic role of the PI3K pathway inGABAergic funcnon. In addinon, our genenc experiments demonstrated that the GABAergic deficit indaf-18 mutants is ennrely dependent on the inacnvanon of the transcripnon factor DAF-16/FOXO.Ketogenic Diets (KDs) have been used since the 1920s for epilepsy who were refractory to GABAergicmedicanons. The mechanisms underlying this therapeunc effect are not understood. We found thatexposure to the ketone body hydroxybutyrate (βHB) during early development ameliorated GABAdefects in daf-18 mutants. Interesnngly, this ketone body does not alleviate the defects observed indaf-16/FOXO mutants, suggesnng an essennal role of this transcripnon factor in the βHB effect. Sincefundamental processes are highly conserved throughout the animal kingdom, this study may contributeto the understanding of disorders associated with imbalances between excitatory and inhibitory signalsin mammals