Modulation of mammalian dendritic GABAA receptor function by the kinetics of Cl− and HCO3− transport

Open Access
Publisher Website
Google Scholar
Abstract
1 During prolonged activation of dendritic GABAA receptors, the postsynaptic membrane response changes from hyperpolarization to depolarization. One explanation for the change in direction of the response is that opposing HCO3− and Cl− fluxes through the GABAA ionophore diminish the electrochemical gradient driving the hyperpolarizing Cl− flux, so that the depolarizing HCO3− flux dominates. Here we demonstrate that the necessary conditions for this mechanism are present in rat hippocampal CA1 pyramidal cell dendrites. 2 Prolonged GABAA receptor activation in low-HCO3− media decreased the driving force for dendritic but not somatic Cl− currents. Prolonged GABAA receptor activation in low-Cl− media containing physiological HCO3− concentrations did not degrade the driving force for dendritic or somatic HCO3− gradients. 3 Dendritic Cl− transport was measured in three ways: from the rate of recovery of GABAA receptor-mediated currents between paired dendritic GABA applications, from the rate of recovery between paired synaptic GABAA receptor-mediated currents, and from the predicted vs. actual increase in synaptic GABAA receptor-mediated currents at progressively more positive test potentials. These experiments yielded estimates of the maximum transport rate (vmax) for Cl− transport of 5 to 7 mmol l−1 s−1, and indicated that vmax could be exceeded by GABAA receptor-mediated Cl− influx. 4 The affinity of the Cl− transporter was calculated in experiments in which the reversal potential for Cl− (ECl) was measured from the GABAA reversal potential in low-HCO3− media during Cl− loading from the recording electrode solution. The calculated KD 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 GABAA depolarizing response in pyramidal cell dendrites.