Cl--GABA System Underlying Modal Shifts from Cellular to Network Oscillations

Abstract

Gamma-aminobutyric acid (GABA) generally induces hyperpolarization and inhibition in the adult brain, but causes depolarization (and can be excitatory) in the immature brain. Because GABAA receptors are Cl- channels, alternating GABA actions between hyperpolarization (Cl- influx) and depolarization (Cl- efflux) are induced by changes in the Cl- gradient, which is regulated by Cl- transporters. Thus, the dynamics of neural functions are modulated by "active" Cl- homeostasis (Cl- homeodynamics), alternating inhibition and excitation, and could be the underlying mechanism of modal shifts in cellular and network oscillations. An ontogenic modal shift in GABA actions is required for normal development, but an aversive reverse modal shift in adults could occur occasionally. Thus any disturbance in this ordinal developmental GABA modal shift, resulting in an abnormal temporal window of depolarizing (excitatory) GABA action, could be the underlying pathogenesis of diverse neurodevelopmental disorders and neurological diseases.