Developmental changes in GABAA tonic inhibition are compromised by multiple mechanisms in preadolescent dentate gyrus granule cells

Abstract

The sustained tonic currents (Itonic) generated by γ-aminobutyric acid A receptors (GABAARs) are implicated in diverse age-dependent brain functions. While various mechanisms regulating Itonic in the hippocampus are known, their combined role in Itonic regulation is not well understood in different age groups. In this study, we demonstrated that a developmental increase in GABA transporter (GAT) expression, combined with gradual decrease in GABAAR a5 subunit, resulted in various Itonic in the dentate gyrus granule cells (DGGCs) of preadolescent rats. Both GAT-1 and GAT-3 expression gradually increased at infantile (P6-8 and P13-15) and juvenile (P20-22 and P 27-29) stages, with stabilization observed thereafter in adolescents (P34-36) and young adults (P41-43). Itonic facilitation of a selective GAT-1 blocker (NO-711) was significantly less at P6-8 than after P13-15. The facilitation of Itonic by SNAP-5114, a GAT-3 inhibitor, was negligible in the absence of exogenous GABA at all tested ages. In contrast, Itonic in the presence of a nonselective GAT blocker (nipecotic acid, NPA) gradually decreased with age during the preadolescent period, which was mimicked by Itonic changes in the presence of exogenous GABA. Itonic sensitivity to L-655,708, a GABAAR a5 subunit inverse agonist, gradually decreased during the preadolescent period in the presence of NPA or exogenous GABA. Finally, Western blot analysis showed that the expression of the GABAAR a5 subunit in the dentate gyrus gradually decreased with age. Collectively, our results suggested that the Itonic regulation of altered GATs is under the final tune of GABAAR a5 subunit activation in DGGCs at different ages.