Neurochlore, Batiment Beret Delaage, Campus Scientifique de Luminy, 13009 Marseille, France.
European Brain Research Institute (EBRI)-Rita Levi-Montalcini, 00161 Roma, Italy.
Cells. 2022 Jan 24;11(3):396. doi: 10.3390/cells11030396.
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]) levels. The control of [Cl] 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.
GABA 使所有动物物种和研究的脑结构中的未成熟神经元去极化并经常兴奋，这是由于细胞内氯离子浓度 ([Cl]) 水平的发育调节降低所致。Cl 水平的控制是由氯离子共转运蛋白 NKCC1 和 KCC2 介导的，前者通常将氯离子导入细胞内，后者将氯离子输出细胞外。在许多实验条件下，使用 NKCC1 氯离子内流抑制剂布美他尼，已经广泛验证了 GABA 极性转变。尽管存在内在异质性，但在许多与发育障碍相关的实验条件下，这种转变会被消除，包括自闭症、雷特综合征、脆性 X 综合征或母体免疫激活。使用布美他尼，一种获得 EMA 和 FDA 批准的药物，许多临床试验已经显示出有希望的结果，同时伴有预期的副作用。Kaila 等人多次对这些实验和临床观察提出质疑。在这里，我们回复了 Kaila 等人的最新评论，强调 GABA 极性转变已被科学界广泛接受，是理解大脑发育的一项重大发现，并且布美他尼在临床试验中显示出了有希望的效果。
