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1Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee; and 2Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, Rockville, Maryland
Submitted 17 June 2004; accepted in final form 3 October 2004
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 co-transporter, drives neuronal Cl– to low concentrations, shifting the GABA reversal potential toward more negative potentials, thus promoting hyperpolarizing GABA responses. Cortical neurons lacking KCC2, not only fail to show a developmental decrease in [Cl–]i, but also are unable to regulate [Cl–]i on 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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