Modulation of mammalian dendritic GABA(A) receptor function by the kinetics of Cl- and HCO3- transport

1. During prolonged activation of dendritic GABA(A) receptors, the postsyna ptic membrane response changes from hyperpolarization to depolarization. On e explanation for the change in direction of the response is that opposing HCO3- and Cl- fluxes through the GABA(A) ionophore diminish the electrochem ical gradient driving the hyperpolarizing Cl- flux, so that the depolarizin g HCO3- flux dominates. Here we demonstrate that the necessary conditions f or this mechanism are present in rat hippocampal CA1 pyramidal cell dendrit es. 2. Prolonged GABA(A) receptor activation in low-HCO3- media decreased the d riving force for dendritic but not somatic Cl- currents. Prolonged GABA(A) receptor activation in low-Cl- media containing physiological HCO3- concent rations did not degrade the driving force for dendritic or somatic HCO3- gr adients. 3. Dendritic Cl- transport was measured in three ways: from the rate of rec overy of GABA(A) receptor-mediated currents between paired dendritic GABA a pplications, from the rate of recovery between paired synaptic GABA(A) rece ptor-mediated currents, and from the predicted vs. actual increase in synap tic GABA(A), receptor-mediated currents at progressively more positive test potentials. These experiments yielded estimates of the maximum transport r ate (upsilon(max)) for Cl- transport of 5 to 7 mmol l(-1) s(-1), and indica ted that upsilon(max) could be exceeded by GABA(A) receptor-mediated Cl- in flux. 4. The affinity of the Cl- transporter was calculated in experiments in whi ch the reversal potential for Cl- (E-Cl) mas measured from the GABA(A) reve rsal potential in low-HCO3- media during Cl- lending from the recording ele ctrode solution. The calculated K-D was 15 mM. 5. Using a standard model of membrane potential, these conditions are demon strated to be sufficient to produce the experimentally observed, activity-d ependent GABA(A) depolarizing response in pyramidal cell dendrites.