Ionic Mechanisms of Neuronal Excitation by Inhibitory GABA$_A$ Receptors

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.