Papers of the Week

In physiological conditions, the intracellular chloride concentration is much lower than the extracellular. As GABA channels are permeable to anions, the reversal potential of GABA is very close to that of Cl, which is the most abundant free anion in the intra- and extracellular spaces. Intracellular chloride is regulated by the activity ratio of NKCC1 and KCC2, two chloride-cation cotransporters that import and export Cl, respectively. Due to the closeness between GABA reversal potential and the value of the resting membrane potential in most neurons, small changes in intracellular chloride have a major functional impact, which makes GABA a uniquely flexible signaling system. In most neurons of the adult brain, the GABA reversal potential is slightly more negative than the resting membrane potential, which makes GABA hyperpolarizing. Alterations in GABA reversal potential are a common feature in numerous conditions as they are the consequence of an imbalance in the NKCC1-KCC2 activity ratio. In most conditions (including Alzheimer’s disease, schizophrenia, and Down’s syndrome), GABA becomes depolarizing, which causes network desynchronization and behavioral impairment. In other conditions (neonatal inflammation and neuropathic pain), however, GABA reversal potential becomes hypernegative, which affects behavior through a potent circuit deactivation.