Homeostatic Competition between Phasic and Tonic Inhibition

The GABA(A) receptors are the major inhibitory receptors in the brain and are localized at both synaptic and extrasynaptic membranes. Synaptic GABA(A) receptors mediate phasic inhibition, whereas extrasynaptic GABA(A) receptors mediate tonic inhibition. Both phasic and tonic inhibitions regulate neuronal activity, but whether they regulate each other is not very clear. Here, we investigated the functional interaction between synaptic and extrasynaptic GABA(A) receptors through various molecular manipulations. Overexpression of extrasynaptic alpha 6 beta 3 delta-GABA(A) receptors in mouse hippocampal pyramidal neurons significantly increased tonic currents. Surprisingly, the increase of tonic inhibition was accompanied by a dramatic reduction of the phasic inhibition, suggesting a possible homeostatic regulation of the total inhibition. Overexpressing the alpha 6 subunit alone induced an up-regulation of delta subunit expression and suppressed phasic inhibition similar to overexpressing the alpha 6 beta 3 delta subunits. Interestingly, blocking all GABA(A) receptors after overexpressing alpha 6 beta 3 delta receptors could not restore the synaptic GABAergic transmission, suggesting that receptor activation is not required for the homeostatic interplay. Furthermore, insertion of a gephyrin-binding-site (GBS) into the alpha 6 beta 3 delta subunits recruited alpha 6(GBS)beta 3 delta(GBS) receptors to postsynaptic sites but failed to rescue synaptic GABAergic transmission. Thus, it is not the positional effect of extrasynaptic alpha 6 beta 3 delta receptors that causes the down-regulation of phasic inhibition. Overexpressing alpha 5 beta 3 gamma 2 subunits similarly reduced synaptic GABAergic transmission. We propose a working model that both synaptic and extrasynaptic GABA(A) receptors may compete for limited receptor slots on the plasma membrane to maintain a homeostatic range of the total inhibition.