GABA_A receptor-mediated tonic depolarization in developing neural circuits

The activation of GABA_A receptors (the type A receptors for γ-aminobutyric acid) produces two distinct forms of responses, phasic (i.e., transient) and tonic (i.e., persistent), that are mediated by synaptic and extrasynaptic GABA_A receptors, respectively. During development, the intracellular chloride levels are high so activation of these receptors causes a net outward flow of anions that leads to neuronal depolarization rather than hyperpolarization. Therefore, in developing neural circuits, tonic activation of GABA_A receptors may provide persistent depolarization. Recently, it became evident that GABA_A receptor-mediated tonic depolarization alters the structure of patterned spontaneous activity, a feature that is common in developing neural circuits and is important for neural circuit refinement. Thus, this persistent depolarization may lead to a long-lasting increase in intracellular calcium level that modulates network properties via calcium-dependent signaling cascades. This article highlights the features of GABA_A receptor-mediated tonic depolarization, summarizes the principles for discovery, reviews the current findings in diverse developing circuits, examines the underlying molecular mechanisms and modulation systems, and discusses their functional specializations for each developing neural circuit.