Excitatory action of GABA on immature neurons is not due to absence of ketone bodies metabolites or other energy substrates

Abstract

SUMMARYBrain slices incubated with glucose have provided most of our knowledge on cellular, synaptic, and network driven mechanisms. It has been recently suggested that c-aminobutyric acid (GABA) excites neonatal neurons in conventional glucose-perfused slices but not when ketone bodies metabolites, pyruvate, and/or lactate are added, suggesting that the excitatory actions of GABA are due to energy deprivation when glucose is the sole energy source. In this article, we review the vast number of studies that show that slices are not energy deprived in glucose-containing medium, and that addition of other energy substrates at physiologic concentrations does not alter the excitatory actions of GABA on neonatal neurons. In contrast, lactate, like other weak acids, can produce an intracellular acidification that will cause a reduction of intracellular chloride and a shift of GABA actions. The effects of high concentrations of lactate, and particularly of pyruvate (4-5 mM), as used are relevant primarily to pathologic conditions; these concentrations not being found in the brain in normal ''control'' conditions. Slices in glucose-containing medium may not be ideal, but additional energy substrates neither correspond to physiologic conditions nor alter GABA actions. In keeping with extensive observations in a wide range of animal species and brain structures, GABA depolarizes immature neurons and the reduction of the intracellular concentration of chloride ([Cl ) ] i ) is a basic property of brain maturation that has been preserved throughout evolution. In addition, this developmental sequence has important clinical implications, notably concerning the higher incidence of seizures early in life and their long-lasting deleterious sequels. Immature neurons have difficulties exporting chloride that accumulates during seizures, leading to permanent increase of [Cl ) ] i that converts the inhibitory actions of GABA to excitatory and hampers the efficacy of GABA-acting antiepileptic drugs.

GABAergic signalling in a neurogenic niche of the turtle spinal cord

“…As a functional correlate of KCC2 immunohistochemical data, we tested the activity of KCC2 in CC‐contacting neurones with different E GABA using a strategy described by Ben‐Ari et al . (2011) in the hippocampus.…”

“…7 and ). The time course of recovery of E GABA reflects the dynamic removal of Cl − by KCC2 (Ben‐Ari et al . 2011; Nardou et al .…”

Synaptic activity-induced Ca2+ signaling in avian cochlear nucleus magnocellularis neurons

“…When an energy substrate enriched ACSF (eACSF containing 5 mM glucose, 5 mM pyruvate, and 2 mM BHB) replaced the standard ACSF, the sign of the reversal potential for GABA in neocortical and hippocampal neurons was reversed, producing conventional hyperpolarizing inhibition (Holmgren et al, 2010). In response to these challenges, a number of studies presented data supporting the classical view of the depolarizing GABA actions during development (Kirmse et al, 2010; Ruusuvuori et al, 2010; Mukhtarov et al, 2011; Tyzio et al, 2011), resulting in exciting ongoing debates on this issue (Zilberter et al, 2010; Ben-Ari et al, 2011; Khakhalin, 2011). Our results (Fig.…”

Searching for new targets for treatment of pediatric epilepsy

“…For example, the immature brain reported to havea depolarizing GABAergic system [16], fewer GABA A receptors [53], lower GABA-mediated currents [54] and is less sensitive to benzodiazepine augmentation [54, 55]. However, the concept of a depolarizing effects of GABA in early-life has been challenged based on recent in vitro studies and earlier in vivo observations suggesting inhibitory activity of GABA in early-life [56, 57](for reviews see [58-60]. …”