title: GABA depolarizes immature neocortical neurons in the presence of the ketone body ß-hydroxybutyrate.
abstract: A large body of evidence suggests that the neurotransmitter GABA undergoes a developmental switch from being predominantly depolarizing-excitatory to predominantly hyperpolarizing-inhibitory. Recently published data, however, point to the possibility that the presumed depolarizing mode of GABA action during early development might represent an artifact due to an insufficient energy supply of the in vitro preparations used. Specifically, addition of the ketone body dl-β-hydroxybutyrate (βHB) to the extracellular medium was shown to prevent GABA from exerting excitatory effects. Applying a complementary set of minimally invasive optical and electrophysiological techniques in brain slices from neonatal mice, we investigated the effects of βHB on GABA actions in immature cells of the upper cortical plate. Fluorescence imaging revealed that GABA-mediated somatic [Ca(2+)] transients, that required activation of GABA(A) receptors and voltage-gated Ca(2+) channels, remained unaffected by βHB. Cell-attached current-clamp recordings showed that, in the presence of βHB, GABA still induced a membrane potential depolarization. To estimate membrane potential changes quantitatively, we used cell-attached recordings of voltage-gated potassium currents and demonstrated that the GABA-mediated depolarization was independent of supplementation of the extracellular solution with βHB. We conclude that, in vitro, GABA depolarizes immature cells of the upper cortical plate in the presence of the ketone body βHB. Our data thereby support the general concept of an excitatory-to-inhibitory switch of GABA action during early development.
authors.affiliation: Experimentelle Neurologie, Hans-Berger-Klinik für Neurologie, Universitätsklinikum Jena, 07747 Jena, Germany. knut.kirmse@med.uni-jena.de
authors.forename: Knut
authors.initials: K
authors.lastname: Kirmse
authors.forename: Otto W
authors.initials: OW
authors.lastname: Witte
authors.forename: Knut
authors.initials: K
authors.lastname: Holthoff
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000494:pharmacology* / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D004357:Drug Synergism; D007657:Ketone Bodies / Q000494:pharmacology / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D019579:Neocortex / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology* / Q000502:physiology
chemical_list: D007657:Ketone Bodies; D005680:gamma-Aminobutyric Acid; D020155:3-Hydroxybutyric Acid