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1 Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA
* To whom correspondence should be addressed. E-mail: eric.delpire{at}vanderbilt.edu.
As excitable cells, neurons experience constant changes in their membrane potential due to ion flux through plasma membrane channels. They maintain their transmembrane cation concentrations through robust Na+/K+-ATPase pump activity. During synaptic transmission and spread of action potentials, the concentration of the major anion, Cl-, is also under constant challenge from membrane potential changes. Moreover, intracellular Cl- is also affected by ligand-gated Cl- channels such as GABAA and glycine receptors. To regulate intracellular Cl- in an electrically silent manner, neurons couple the movement of Cl- with K+. In this study, we have used gene-targeted KCC2-/- mice to provide strong evidence that KCC2, the neuronal-specific K-Cl cotransporter, drives neuronal Cl- to low concentrations, shifting the GABA reversal potential towards more negative potentials, thus promoting hyperpolarizing GABA responses. Cortical neurons lacking KCC2, not only fail to demonstrate a developmental decrease in [Cl-]i, but also are unable to regulate [Cl-]i upon Cl- loading, or maintain [Cl-]i during membrane depolarization. These data are consistent with the central role of KCC2 in promoting inhibition and preventing hyperexcitability.
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