Modulation of mammalian dendritic GABA A receptor function by the kinetics of Cl − and HCO 3 − transport

1 During prolonged activation of dendritic GABA A receptors, the postsynaptic membrane response changes from hyperpolarization to depolarization. One explanation for the change in direction of the response is that opposing HCO 3 − and Cl − fluxes through the GABA A ionophore diminish the electrochemical gradient driving the hyperpolarizing Cl − flux, so that the depolarizing HCO 3 − flux dominates. Here we demonstrate that the necessary conditions for this mechanism are present in rat hippocampal CA1 pyramidal cell dendrites. 2 Prolonged GABA A receptor activation in low‐HCO 3 − media decreased the driving force for dendritic but not somatic Cl − currents. Prolonged GABA A receptor activation in low‐Cl − media containing physiological HCO 3 − concentrations did not degrade the driving force for dendritic or somatic HCO 3 − gradients. 3 Dendritic Cl − transport was measured in three ways: from the rate of recovery of GABA A receptor‐mediated currents between paired dendritic GABA applications, from the rate of recovery between paired synaptic GABA A receptor‐mediated currents, and from the predicted vs. actual increase in synaptic GABA A receptor‐mediated currents at progressively more positive test potentials. These experiments yielded estimates of the maximum transport rate ( v max ) for Cl − transport of 5 to 7 mmol l −1 s −1 , and indicated that v max could be exceeded by GABA A receptor‐mediated Cl − influx. 4 The affinity of the Cl − transporter was calculated in experiments in which the reversal potential for Cl − ( E Cl ) was measured from the GABA A reversal potential in low‐HCO 3 − media during Cl − loading from the recording electrode solution. The calculated K D was 15 mM. 5 Using a standard model of membrane potential, these conditions are demonstrated to be sufficient to produce the experimentally observed, activity‐dependent GABA A depolarizing response in pyramidal cell dendrites.