Abstract
GABA depolarizes and often excites immature neurons in all animal species and brain structures investigated due to a developmentally regulated reduction in intracellular chloride concentration ([Cl−]i) levels. The control of [Cl−]i levels is mediated by the chloride cotransporters NKCC1 and KCC2, the former usually importing chloride and the latter exporting it. The GABA polarity shift has been extensively validated in several experimental conditions using often the NKCC1 chloride importer antagonist bumetanide. In spite of an intrinsic heterogeneity, this shift is abolished in many experimental conditions associated with developmental disorders including autism, Rett syndrome, fragile X syndrome, or maternal immune activation. Using bumetanide, an EMA- and FDA-approved agent, many clinical trials have shown promising results with the expected side effects. Kaila et al. have repeatedly challenged these experimental and clinical observations. Here, we reply to the recent reviews by Kaila et al. stressing that the GABA polarity shift is solidly accepted by the scientific community as a major discovery to understand brain development and that bumetanide has shown promising effects in clinical trials.
Highlights
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GDPs disappear when the polarity of GABA shifts from the depolarizing to the hyperpolarizing direction. These observations (Figure 1) indicate that the actions of GABA follow a developmental course with a significant polarity shift of its actions, and this underlies major changes in cell and network activity
It bears stressing that oxytocin controls the GABA excitatory-to-inhibitory shift [28], plasma oxytocin levels are lower in children with autism spectrum disorders (ASDs) [29], sensitive parenting is impacted by oxytocin [30], and intranasal oxytocin attenuates social deficits in patients with ASDs [31]
Summary
In 1989, recording from hundreds of neonatal rat hippocampal slices, we made three completely unexpected observations [1]. GDPs disappear when the polarity of GABA shifts from the depolarizing to the hyperpolarizing direction These observations (Figure 1) indicate that the actions of GABA follow a developmental course with a significant polarity shift of its actions, and this underlies major changes in cell and network activity. The GABA developmental polarity shift became a major topic of investigation, providing considerable advances in understanding its underlying mechanisms and biological significance, notably in relation to the trophic actions of GABA [5,6,7,8,9]. Our aim is to challenge what we consider a dogmatic biased view on what has been or ought to be carried out to understand the GABA polarity shift and its experimental or clinical implications
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