Egr3 stimulation of GABRA4 promoter activity as a mechanism for seizure-induced up-regulation of GABA(A) receptor alpha4 subunit expression.

GABA is the major inhibitory transmitter at CNS synapses. Changes in subunit composition of the pentameric GABA(A) receptor, including increased levels of alpha4 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 alpha4 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 alpha4 subunit containing GABA(A) receptors. 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 alpha4 subunits. Given that Egr3 knockout mice display approximately 50% less GABRA4 mRNAs in the hippocampus and that increases in alpha4 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.