Evidence that GABAA receptor subunit mRNA expression during development is regulated by GABAA receptor stimulation.
The expression of six mRNA species (alpha 2, alpha 3, alpha 5, beta 2, beta 3, and gamma 2) encoding for GABAA receptor subunits was followed in cultured early postnatal cortical neurons by in situ hybridization histochemistry. In untreated control cultures it was found that these subunit mRNA expression profiles closely follow those seen during development in vivo. alpha 3, alpha 5, and beta 3 subunit expression declined, alpha 2 expression increased, whereas beta 2 and gamma 2 subunit mRNA expression remained relatively constant. To test the hypothesis that GABAA receptor stimulation regulates these expression profiles, we tested the effect of a GABAA receptor positive modulator, allopregnanolone, and a GABAA receptor noncompetitive antagonist, tert-butylbicyclophosphorothionate (TBPS). It was found that allopregnanolone augmented the rate at which the alpha 3, alpha 5, or beta 3 subunit mRNA expression declined and prevented the increase in alpha 2 subunit mRNA expression. As well, allopregnanolone down-regulated beta 2 subunit mRNA expression. TBPS, on the other hand, up-regulated alpha 3, alpha 5, beta 2, and beta 3 subunit mRNA expression. It also down-regulated the expression of alpha 2 subunit mRNA. Both allopregnanolone and TBPS had no effect on gamma 2 subunit mRNA expression. These results imply that the developmental switchover of GABA receptor subunit mRNA expression is regulated by GABAA receptor activity.
Poulter
M O
MO
Institut de Physiologie, Université Louis Pasteur, Strasbourg, France.
Ohannesian
L
L
Larmet
Y
Y
Feltz
P
P
D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured / Q000737:chemistry / Q000502:physiology; D002540:Cerebral Cortex / Q000166:cytology; D003292:Convulsants / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology; D011280:Pregnanolone / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000737:chemistry / Q000235:genetics*
D019086:Bridged Bicyclo Compounds, Heterocyclic; D003292:Convulsants; D018757:GABA Modulators; D058785:GABA-A Receptor Agonists; D012333:RNA, Messenger; D011963:Receptors, GABA-A; C037476:tert-butylbicyclophosphorothionate; D011280:Pregnanolone