Neurobiology Sector and IIT Unit, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136, Trieste, Italy.
Mol Neurobiol. 2011 Apr;43(2):97-106. doi: 10.1007/s12035-010-8147-z. Epub 2010 Nov 3.
Early in postnatal life γ-aminobutyric acid (GABA), the primary inhibitory transmitter in adults, excites targeted neurons by an outwardly directed flux of chloride which results from the unbalance between the cation-chloride cotransporters NKCC1 and KCC2, involved in chloride uptake and extrusion, respectively. This effect contributes to generate synchronized network activity or giant depolarizing potentials (GDPs) in the developing hippocampus. Here, we review some recent data concerning the mechanisms by which GDPs are generated and their functional role in enhancing synaptic efficacy at poorly developed GABAergic and glutamatergic synapses. In adulthood, reshaping neuronal circuits due to changes in chloride homeostasis and to the shift of GABA from hyperpolarizing to depolarizing, has been implicated in several neurological disorders, including epilepsy. Evidence has been recently provided that in chronically nerve growth factor-deprived mice expressing a progressive age-dependent neurodegenerative pathology resembling that observed in patients with Alzheimer's disease, the reduced expression of mRNA encoding for the Kcc2 gene and the depolarizing action of GABA lead to the reorganization of the neuronal hippocampal network. This may represent a novel mechanism by which GABAergic signaling counterbalances the loss of synaptic activity in neurodegenerative diseases.
在生命早期，γ-氨基丁酸（GABA）作为成人主要的抑制性递质，通过 NKCC1 和 KCC2 之间的失衡，导致氯离子外向转运，从而兴奋靶向神经元，这两种阳离子-氯离子共转运体分别参与氯离子的摄取和外排。这种作用有助于在发育中的海马体中产生同步的网络活动或巨化去极化电位（GDPs）。在这里，我们回顾了一些最近的数据，这些数据涉及 GDPs 的产生机制及其在增强发育不良的 GABA 能和谷氨酸能突触的突触效能方面的功能作用。在成年期，由于氯离子动态平衡的变化以及 GABA 从超极化到去极化的转变，神经元回路的重塑与包括癫痫在内的几种神经疾病有关。最近有证据表明，在慢性神经生长因子剥夺的小鼠中，表达一种进行性的、与阿尔茨海默病患者观察到的相似的年龄依赖性神经退行性病理，编码 Kcc2 基因的 mRNA 表达减少和 GABA 的去极化作用导致了海马神经元网络的重组。这可能代表了一种新的机制，通过这种机制，GABA 能信号可以平衡神经退行性疾病中突触活动的丧失。
