GABAA receptor modulation by ketone bodies

PARLATO MI; DI MARTINO T; LÓPEZ PAZOS, MANUEL I; DEL VAS M; BELTRÁN GONZÁLEZ ANDREA; CALVO DJ

Congreso; Reunión Anual de las Sociedades de Biociencias SAIC SAI SAFIS 2020; 2020

SAIC SAI SAFIS

Ketone bodies are produced from the β-oxidation of fatty acids during ketogenesis. In humans, acetyl-CoA is the end product of fatty acid catabolism. Three types of ketone bodies can be synthesized from acetyl-CoA: acetone, β-hydroxybutyrate and acetoacetate. Ketogenesis is increased under conditions of low glucose (eg, fasting), low insulin or excessive alcohol consumption. This increase also occurs during certain diets, with low carbohydrate and high fat consumption, indicated to reduce the probability of seizures in epileptic patients or to alleviate the alcohol withdrawal syndrome. Additional beneficial effects of ketogenic diets have been described in models of Alzheimer´s disease and amyotrophic lateral sclerosis. The actions of ketone bodies on neurotransmission have been poorly explored and the mechanisms responsible for the therapeutic benefits of ketogenic diets remain under study.Recently Pflanz et al. (2019) studied for the first time the effects of ketone bodies on ligand-activated ion channels and described acetone as a positive modulator and β-hydroxybutyrate as a negative modulator of GABAAα1β2γ2 receptors. In this context, we studied the modulatory effects of ketone bodies on GABAergic neurotransmission, evaluating the sensitivity of different subtypes of GABAA phasic and tonic receptors. Human GABAAρ1, GABAAα1β2, GABAAα5β3 y GABAAα4β3δ were expressed in Xenopus laevis oocytes and chloride currents were recorded by two-electrode voltage-clamp. Results with acetone (100 to 300 mM) showed inhibitory effects on GABAAρ1 and potentiating effects on GABAAα1β2, GABAAα5β3 and GABAAα4β3δ responses (~EC10). Acetone effects on oocytes baseline were controlled in every experiment. Further experiments will be carried out to characterize acetone modulation and evaluate β-hydroxybutyrate effects on these receptors.