Activity-dependent intracellular chloride accumulation and diffusion controls GABAA receptor-mediated synaptic transmission

In the CNS, prolonged activation of GABAA receptors (GABAARs) has been shown to evoke biphasic postsynaptic responses, consisting of an initial hyperpolarization followed by a depolarization. A potential mechanism underlying the depolarization is an acute chloride (Cl−) accumulation resulting in a shift of the GABAA reversal potential (EGABA). The amount of GABA-evoked Cl− accumulation and accompanying depolarization depends on presynaptic and postsynaptic properties of GABAergic transmission, as well as on cellular morphology and regulation of Cl− intracellular concentration ([Cl−]i). To analyze the influence of these factors on the Cl− and voltage behavior, we studied spatiotemporal dynamics of activity-dependent [Cl−]i changes in multicompartmental models of hippocampal cells based on realistic morphological data. Simulated Cl− influx through GABAARs was able to exceed physiological Cl− extrusion rates thereby evoking HCO3− -dependent EGABA shift and depolarizing responses. Depolarizations were observed in spite of GABAA receptor desensitization. The amplitude of the depolarization was frequency-dependent and determined by intracellular Cl− accumulation. Changes in the dendritic diameter and in the speed of GABA clearance in the synaptic cleft were significant sources of depolarization variability. In morphologically reconstructed granule cells subjected to an intense GABAergic background activity, dendritic inhibition was more affected by accumulation of intracellular Cl− than somatic inhibition. Interestingly, EGABA changes induced by activation of a single dendritic synapse propagated beyond the site of Cl− influx and affected neighboring synapses. The simulations suggest that EGABA may differ even along a single dendrite supporting the idea that it is necessary to assign EGABA to a given GABAergic input and not to a given neuron. © 2010 Wiley-Liss, Inc.