Cell type- and synapse-specific variability in synaptic GABA(A) receptor occupancy

The degree of postsynaptic type A gamma-aminobutyric acid receptor (GABA(A) receptor) occupancy was investigated by using the benzodiazepine agonist zolpidem. This drug increases the affinity of GABA(A) receptors for gamma-aminobutyric acid (GABA) at room temperature (Perrais & Ropert 1999, J. Neurosci., 19, 578) leading to an enhancement of synaptic current amplitudes if receptors are not fully occupied by the released transmitter. We recorded miniature inhibitory postsynaptic currents (mIPSCs) from eight different cell types in three brain regions of rats and mice. Receptors in every cell type were benzodiazepine sensitive, as 10-20 mu m zolpidem prolonged the decays of mIPSCs (151-184% of control). The amplitude of the GABA(A) receptor-mediated events was significantly enhanced in dentate granule cells, CA1 pyramidal cells, hippocampal GABAergic interneurons, cortical layer V pyramidal cells, cortical layer V interneurons, and in cortical layer II/III interneurons. An incomplete postsynaptic GABA(A) receptor occupancy is thus predicted in these cells. In contrast, zolpidem induced no significant change in mIPSC amplitudes recorded from layer II/III pyramidal cells, suggesting full GABA(A) receptor occupancy. Moreover, different degrees of receptor occupancy could be found at distinct GABAergic synapses on a given cell. For example, of the two distinct populations of zolpidem-sensitive mIPSCs recorded in olfactory bulb granule cells, the amplitude of only one type was significantly enhanced by the drug. Thus, at synapses that generate mIPSCs, postsynaptic receptor occupancy is cell type and synapse specific, reflecting local differences in the number of receptors or in the transmitter concentration in the synaptic cleft.