GABA neurotransmission and neural cation-chloride co-transporters: actions beyond ion transport

During neuronal development, gamma-aminobutyric acid (GABA), which is the principal inhibitory neurotransmitter in the mature brain, exerts a paradoxical depolarizing action that plays an important role in the generation of neuronal synaptic activities in the immature cortical structures and in the formation of the neuronal network. The depolarizing action of GABA is due to a differential organization of the chloride homeostasis system; in immature neurons it maintains an elevated intracellular chloride concentration ([Cl-]i), whereas in mature neurons it keeps [Cl-]i at relatively low levels. Several recent studies have shown that the function of chloride transporters during neuronal development extends beyond the simple maintenance of chloride homeostasis and might play an active role in neuronal growth and formation of synaptic connections. In the present manuscript, we summarize such evidence and discuss the perspectives in the study of the functional role of ion transporters in determining the mode of GABA actions.