Bidirectional Regulation of GABA_A Reversal Potential in the Adult Brain: Physiological and Pathological Implications

In physiological conditions, the intracellular chloride concentration is much lower than the extracellular. As GABA_A channels are permeable to anions, the reversal potential of GABA_A 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_A 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 a uniquely flexible signaling system. In most neurons of the adult brain, the GABA_A reversal potential is slightly more negative than the resting membrane potential, which makes GABA_A hyperpolarizing. Alterations in GABA_A 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_A becomes depolarizing, which causes network desynchronization and behavioral impairment. In other conditions (neonatal inflammation and neuropathic pain), however, GABA_A reversal potential becomes hypernegative, which affects behavior through a potent circuit deactivation.