Egr3 Stimulation of GABRA4 Promoter Activity as a Mechanism for Seizure-Induced Up-Regulation of GABAAReceptor α4 Subunit Expression

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 33; pp. 11894 - 11899
• Main Authors: Roberts, D. S., Raol, Y. H., Bandyopadhyay, S., Lund, I. V., Budreck, E. C., Passini, M. J., Wolfe, J. H., Brooks-Kayal, A. R., Russek, S. J., Costa, Erminio
• Format: Journal Article
• Language: English
• Published: National Academy of Sciences 16.08.2005
• Subjects: Biological Sciences; Complementary DNA; Dentate gyrus; Hippocampus; Messenger RNA; Neurons; Rats; Receptors; Seizures; Small interfering RNA; Viruses
• ISSN: 0027-8424; 1091-6490

GABA is the major inhibitory transmitter at CNS synapses. Changes in subunit composition of the pentameric GABAAreceptor, including increased levels of α4 subunit in dentate granule cells and associated functional alterations such as increased zinc blockade of GABA currents, are hypothesized to be critical components of epileptogenesis. Here, we report that the minimal promoter of the human α4 subunit gene (GABRA4p), when used to drive reporter gene expression from adeno-associated viral vectors, controls condition-specific up-regulation in response to status epilepticus, defining a transcriptional mechanism for seizure-induced changes in levels of α4 subunit containing GABAAreceptors. Transfection studies in primary hippocampal neurons show that inducible early growth response factor 3 (Egr3) up-regulates GABRA4p activity as well as the levels of endogenous α4 subunits. Given that Egr3 knockout mice display ≈50% less GABRA4 mRNAs in the hippocampus and that increases in α4 and Egr3 mRNAs in response to pilocarpine-induced status epilepticus are accompanied by increased binding of Egr3 to GABRA4 in dentate granule cells, our findings support a role for Egr3 as a major regulator of GABRA4 in developing neurons and in epilepsy.