Which GABAA receptor subunits are necessary for tonic inhibition in the hippocampus?

GABA(A) receptors (GABA(A)Rs) assembled of different subunits mediate tonic and phasic inhibition in hippocampal neurons. CA1/CA3 pyramidal cells (PCs) predominantly express alpha 5 subunits whereas dentate gyrus granule cells (DGGCs) and molecular layer (ML) interneurons predominantly express delta subunits. Both alpha 5- and delta-containing GABAARs mediate tonic inhibition. We have shown previously that mice lacking alpha 5 subunits (Gabra5(-/-)) have a residual tonic current in CA1/CA3 PCs because of an upregulation of delta subunits, but the basis of the residual tonic current in DGGCs and ML interneurons of mice lacking the delta subunit (Gabrd(-/-)) is still unknown. We now show that wild-type DGGCs have a small tonic current mediated by alpha 5 subunit-containing GABA(A)Rs responsible for similar to 29% of the total tonic current. To better identify the GABAARs mediating tonic inhibition in hippocampal neurons, we generated mice lacking both alpha 5 and delta subunits (Gabra5/Gabrd(-/-)). Recordings from CA1/CA3 PCs, DGGCs, and ML interneurons in these mice show an absence of tonic currents without compensatory changes in spontaneous IPSCs (sIPSCs), sEPSCs, and membrane resistance. The absence of tonic inhibition results in spontaneous gamma oscillations recordable in vitro in the CA3 pyramidal layer of these mice, which can be mimicked in wild-type mice by blocking alpha 5 subunit-containing GABAARs with 50 nM L-655,708. In conclusion, depending on the cell type, the alpha 5 and delta subunits are the principal GABA(A)R subunits responsible for mediating the lion's share of tonic inhibition in hippocampal neurons.