Virally-induced expression of GABAA receptor δ subunits following their pathological loss reveals their role in regulating GABAA receptor assembly

Decreased expression of the delta subunit of the GABA(A) receptor (GABA(A)R) has been found in the dentate gyrus in several animal models of epilepsy and other disorders with increased excitability and is associated with altered modulation of tonic inhibition in dentate granule cells (GCs). In contrast, other GABA(A)R subunits, including alpha 4 and gamma 2 subunits, are increased, but the relationship between these changes is unclear. The goals of this study were to determine if viral transfection of delta subunits in dentate GCs could increase delta subunit expression, alter expression of potentially-related GABA(A)R subunits, and restore more normal network excitability in the dentate gyrus in a mouse model of epilepsy. Pilocarpine-induced seizures were elicited in DOCK10-Cre mice that express Cre selectively in dentate GCs, and two weeks later the mice were injected unilaterally with a Cre-dependent delta-GABA(A)R viral vector. At 4-6 weeks following transfection, delta subunit immunolabeling was substantially increased in dentate GCs on the transfected side compared to the nontransfected side. Importantly, alpha 4 and gamma 2 subunit labeling was downregulated on the transfected side. Electrophysiological studies revealed enhanced tonic inhibition, decreased network excitability, and increased neurosteroid sensitivity in slices from the delta subunit-transfected side compared to those from the nontransfected side of the same pilocarpine-treated animal, consistent with the formation of delta subunit-containing GABA(A)Rs. No differences were observed between sides of eYFP-transfected animals. These findings are consistent with the idea that altering expression of key subunits, such as the delta subunit, regulates GABA(A)R subunit assemblies, resulting in substantial effects on network excitability.

Automated summary

The decreased expression of the delta subunit of the GABA(A) receptor has been found to be associated with altered modulation of tonic inhibition in dentate granule cells in animal models of epilepsy and other disorders. This study aimed to investigate if viral transfection of delta subunits could restore network excitability in a mouse model of epilepsy. The results showed that transfection of delta subunits increased delta subunit expression, downregulated other GABA(A) receptor subunits, and restored more normal network excitability.