Developmental changes in GABA_A tonic inhibition are compromised by multiple mechanisms in preadolescent dentate gyrus...

The sustained tonic currents (I_tonic) generated by γ-aminobutyric acid A receptors (GABA_ARs) are implicated in diverse age-dependent brain functions. While various mechanisms regulating I_tonic in the hippocampus are known, their combined role in I_tonic 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 GABA_AR α₅ subunit, resulted in various I_tonic in the dentate gyrus granule cells (DGGCs) of preadolescent rats. Both GAT-1 and GAT-3 expression gradually increased at infantile (P_6-8 and P_13-15) and juvenile (P_20-22 and P_27-29) stages, with stabilization observed thereafter in adolescents (P_34-36) and young adults (P_41-43). I_tonic facilitation of a selective GAT-1 blocker (NO-711) was significantly less at P_6-8 than after P_13-15. The facilitation of I_tonic by SNAP-5114, a GAT-3 inhibitor, was negligible in the absence of exogenous GABA at all tested ages. In contrast, I_tonic in the presence of a nonselective GAT blocker (nipecotic acid, NPA) gradually decreased with age during the preadolescent period, which was mimicked by I_tonic changes in the presence of exogenous GABA. I_tonic sensitivity to L-655,708, a GABA_AR α₅ 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 GABA_AR α₅ subunit in the dentate gyrus gradually decreased with age. Collectively, our results suggested that the I_tonic regulation of altered GATs is under the final tune of GABA_AR α₅ subunit activation in DGGCs at different ages.