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 bendritic GABA(A) receptor activation is excitatory or inhibitory.