The physiological role of KCC2 in the cerebellum

Abstract

Cation chloride cotransporters mediate a coupled electroneutral movement of Cl−, K+ and Na+ across plasmamembranes in many cells. The neuron-specific KCl cotransporter KCC2 is thought to lower the intracellular Cl− concentration below its electrochemical equilibrium potential by using the outwards directed gradient of K+ as a driving force. This low intracellular Cl− concentration is required for the fast inhibitory action of GABA which is mediated by the GABAA receptor, a ligand-gated anion channel. The activation of GABAA receptors drives the membrane potential of a cell towards EGABA, the reversal potential of GABAergic currents. In immature neurons, GABA is excitatory, as EGABA is above the resting membrane po- tential. The expression of KCC2 correlates with the drop of EGABA below the resting membrane potential, and thereby the switch from excitatory to inhibi- tory GABA signaling. The KCl cotransporter KCC3 is expressed more broadly and involved in cell volume regulation. Nevertheless, while KCC2 may be the key regulator of neu- ronal [Cl−]i, a similar role was proposed for KCC3. We investigate the physi- ological role of KCC2 and KCC3 in the murine cerebellum at cellular level via the patch clamp technique in acute slices. We showed that knocking out KCC2 in cerebellar Purkinje cells results in a shift of EGABA, which could be corre- lated with motor learning deficits