Cellular Mechanisms of Neuronal Cl− Homeostasis and its Modulation by Neuronal Injury
The function of the brain depends on the fine balance between inhibition and excitation of neurons. The polarity and amplitude of an inhibitory synaptic response depends on both the relative permeability of the receptor-channels involved, and also on the driving force for the permeant ions which is established by an array of active membrane transport proteins. At inhibitory synapses, the cation chloride co-transporters, including NKCC1 and KCC2, are particularly important in determining intracellular Cl− concentrations and the efficacy of inhibitory synaptic responses. Recent experiments have shown that the expression and activity of these transporters can change, not only over development, but also in response to neuronal injury. In this article, we review the basic biophysical aspects and role of different transporters in neuronal Cl− homeostasis and how the expression and function of these transporters, particularly KCC2, changes during development and in response to a wide range of models of neuronal injury. We also review recent data regarding the cellular and molecular mechanisms by which injury induced changes in KCC2 function may occur. Our review hopes to highlight the need for further investigation of these processes, to enable a greater understanding of developmental and pathological plasticity at inhibitory synapses, and to enable the potential development of novel therapeutic strategies to treat neuronal dysfunction.
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