δ subunit-containing GABAA IPSCs are driven by both synaptic and diffusional GABA in mouse dentate granule neurons.

GABAA receptors mediate transmission throughout the central nervous system and typically contain a δ subunit (δ receptors) or a γ2 subunit (γ2 receptors). δ IPSCs decay slower than γ2 IPSCs, but the reasons are unclear. Transmitter diffusion, rebinding, or slow deactivation kinetics of channels are candidates. We used gene editing to confer picrotoxin resistance on δ receptors in mice, then pharmacologically isolated δ receptors in mouse dentate granule cells to explore IPSCs. γ2 and δ components of IPSCs were modulated similarly by presynaptic manipulations and manipulations of transmitter lifetime, suggesting that GABA release recruits δ receptors proportionally to γ2 receptors. δ IPSCs showed more sensitivity to altered transmitter release and to a rapidly dissociating antagonist, suggesting an additional spillover contribution. Reducing GABA diffusion with 5% dextran increased the peak amplitude and decreased the decay of evoked δ IPSCs but had no effect on δ or dual-component (mainly γ2-driven) spontaneous IPSCs, suggesting that GABA actions can be local for both receptor types. Rapid application of varied [GABA] onto nucleated patches from dentate granule cells demonstrated a deactivation rate of δ receptors similar to that of δ spontaneous IPSCs, consistent with the idea that deactivation and local GABA actions drive δ spontaneous IPSCs. Overall, our results indicate that δ IPSCs are activated by both synaptic and diffusional GABA. Our results are consistent with a functional relationship between δ and γ2 GABAA receptors akin to that of slow NMDA and fast AMPA EPSCs at glutamate synapses.