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

• Published in: The Korean journal of physiology & pharmacology Vol. 21; no. 6; pp. 695 - 702
• Main Authors: Pandit, Sudip, Lee, Gyu Seung, Park, Jin Bong
• Format: Journal Article
• Language: English
• Published: The Korean Physiological Society and The Korean Society of Pharmacology 01-11-2017; 대한약리학회
• Subjects: Original; 약리학
• ISSN: 1226-4512; 2093-3827
• DOI: 10.4196/kjpp.2017.21.6.695

The sustained tonic currents (I
tonic
) generated by γ-aminobutyric acid A receptors (GABA
A
Rs) 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
A
R α
5
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
A
R α
5
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
A
R α
5
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
A
R α
5
subunit activation in DGGCs at different ages.