Which GABA(A) 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 alpha5 subunits whereas dentate gyrus granule cells (DGGCs) and molecular layer (ML) interneurons predominantly express delta subunits. Both alpha5- and delta-containing GABA(A)Rs mediate tonic inhibition. We have shown previously that mice lacking alpha5 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 alpha5 subunit-containing GABA(A)Rs responsible for approximately 29% of the total tonic current. To better identify the GABA(A)Rs mediating tonic inhibition in hippocampal neurons, we generated mice lacking both alpha5 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 alpha5 subunit-containing GABA(A)Rs with 50 nM L-655,708. In conclusion, depending on the cell type, the alpha5 and delta subunits are the principal GABA(A)R subunits responsible for mediating the lion's share of tonic inhibition in hippocampal neurons.