Chloride homeodynamics underlying modal shifts in cellular and network oscillations

Abstract

γ-Aminobutyric acid (GABA) generally induces hyperpolarization and inhibition in the adult brain, but causes depolarization (and can be excitatory) in the immature brain. Depolarizing GABA actions are necessary for neurogenesis, differentiation, migration, and synaptogenesis. Additionally, the conversion of GABA responses from inhibition to excitation can be induced in adults by pathological conditions. Because GABA_A 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 C^- transporters. Thus, the dynamics of neural functions are modulated by active Cl^- homeostasis (Cl^- homeodynamics), alternating inhibition and excitation, and could underlie the modal shifts in cellular and network oscillations. Such a modal shift in GABA actions is required for normal development. Thus disturbances in this developmental GABA modal shift and/or the induction of excitatory GABA action in adult could underlie the pathogenesis of diverse neurological diseases (so-called network diseases).

Keywords: Cation-chloride cotransporter; Cl(−) homeostasis; GABA; KCC2; NKCC1; Neurodevelopmental disorders; Neurological diseases; Oscillology.