Ionic Mechanisms of Neuronal Excitation by Inhibitory GABA A Receptors

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Abstract
Gamma-aminobutyric acid A (GABA A ) receptors are the principal mediators of synaptic inhibition, and yet when intensely activated, dendritic GABA A receptors excite rather than inhibit neurons. The membrane depolarization mediated by GABA A receptors is a result of the differential, activity-dependent collapse of the opposing concentration gradients of chloride and bicarbonate, the anions that permeate the GABA A ionophore. Because this depolarization diminishes the voltage-dependent block of the N -methyl-D-aspartate (NMDA) receptor by magnesium, the activity-dependent depolarization mediated by GABA is sufficient to account for frequency modulation of synaptic NMDA receptor activation. Anionic gradient shifts may represent a mechanism whereby the rate and coherence of synaptic activity determine whether dendritic GABA A receptor activation is excitatory or inhibitory.