The physiological role of KCC2 in the cerebellum.

PATRICIA SEJA; GUILLERMO SPITZMAUL; CARSTEN PFEFFER; THOMAS J. JENTSCH

Berlin

Simposio; Berlin Brain Days 2009; 2009

Max Delbrück Centrum füu Molekulare Dedizin

Cation chloride cotransporters mediate a coupled electroneutral movement of Cl-, K+ and Na+ across plasma membranes in many cells. The neuron-specific K-Cl cotransporter KCC2 is thought to lower 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 potential. The expression of KCC2 correlates with the drop of EGABA below the resting membrane potential, and thereby the switch from excitatory to inhibitory GABA signaling. The K-Cl cotransporter KCC3 is expressed more broadly and involved in cell volume regulation. Nevertheless, while KCC2 may be the key regulator of neuronal intracellular chloride concentration, a similar role was proposed for KCC3. We investigate the physiological 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 the cerebellar Purkinje cells results in a shift of EGABA, which could be correlated with motor learning deficits.