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Ionic currents and the network-driven patterns they generate differ in immature and adult neurons: The developing brain is not a “small adult brain.” One of the most investigated examples is the developmentally regulated shift of actions of the transmitter GABA that inhibit adult neurons but excite immature ones because of an initially higher intracellular chloride concentration [Cl(-)](i), leading to depolarizing and often excitatory actions of GABA instead of hyperpolarizing and inhibitory actions. The levels of [Cl(-)](i) are also highly labile, being readily altered transiently or persistently by enhanced episodes of activity in relation to synaptic plasticity or a variety of pathological conditions, including seizures and brain insults. Among the plethora of channels, transporters, and other devices involved in controlling [Cl(-)](i), two have emerged as playing a particularly important role: the chloride importer NKCC1 and the chloride exporter KCC2. Here, the authors stress the importance of determining how [Cl(-)](i) is dynamically regulated and how this affects brain operation in health and disease. In a clinical perspective, agents that control [Cl(-)](i) and reinstate inhibitory actions of GABA open novel therapeutic perspectives in many neurological disorders, including infantile epilepsies, autism spectrum disorders, and other developmental disorders.

Yehezkel Ben-Ari  ¹ , Ilgam Khalilov, Kristopher T Kahle, Enrico Cherubini