Dendrite-targeting interneurons control synaptic NMDA-receptor activation via nonlinear α5-GABA_A receptors

Dendrite-targeting GABAergic interneurons powerfully control postsynaptic integration, synaptic plasticity, and learning. However, the mechanisms underlying the efficient GABAergic control of dendritic electrogenesis are not well understood. Using subtype-selective blockers for GABA_A receptors, we show that dendrite-targeting somatostatin interneurons and NO-synthase-positive neurogliaform cells preferentially activate α5-subunit- containing GABA_A receptors (α5-GABA_ARs), generating slow inhibitory postsynaptic currents (IPSCs) in hippocampal CA1 pyramidal cells. By contrast, only negligible contribution of these receptors could be found in perisomatic IPSCs, generated by fast-spiking parvalbumin interneurons. Remarkably, α5-GABA_AR-mediated IPSCs were strongly outward-rectifying generating 4-fold larger conductances above -50 mV than at rest. Experiments and modeling show that synaptic activation of these receptors can very effectively control voltage-dependent NMDA-receptor activation as well as Schaffer-collateral evoked burst firing in pyramidal cells. Taken together, nonlinear-rectifying α5-GABA_ARs with slow kinetics match functional NMDA-receptor properties and thereby mediate powerful control of dendritic postsynaptic integration and action potential firing by dendrite-targeting interneurons.