GABA_A receptor α5 subunits contribute to GABA _A,slow synaptic inhibition in mouse hippocampus

γ-Aminobutyric acid type A (GABA_A) receptor α5 subunits, which are heavily expressed in the hippocampus, are potential drug targets for improving cognitive function. They are found at synaptic and extrasynaptic sites and have been shown to mediate tonic inhibition in pyramidal neurons. We tested the hypothesis that α5 subunits also contribute to synaptic inhibition by measuring the effect of diazepam (DZ) on spontaneous and stimulus-evoked inhibitory postsynaptic currents (IPSCs) in genetically modified mice carrying a point mutation in the α5 subunit (α5-H105R) that renders those receptors insensitive to benzodiazepines. In wild type mice, DZ (1 μM) increased the amplitude of spontaneous IPSCs (sIPSCs) and stimulus-evoked GABA_A,slow IPSCs (eIPSCs) and prolonged the decay of GABA_A,fast sIPSCs. In α5-mutant mice, DZ increased the amplitude of a small-amplitude subset of sIPSCs (<50 pA) and eIPSCs (<300 pA) GABA_A,slow and prolonged the decay of GABA_A,fast sIPSCs, but failed to increase the amplitude of larger sIPSCs and eIPSCs GABA_A,slow. These results indicate that α5 subunits contribute to a large-amplitude subset of GABA_A,slow synapses and implicate these synapses in modulation of cognitive function by drugs that target α5 subunits.