Early growth response 1 (Egr-1) directly regulates GABAA receptor α2, α4, and θ subunits in the hippocampus.

Abstract

The homeostatic regulation of neuronal activity in glutamatergic and GABAergic synapses is critical for neural circuit development and synaptic plasticity. The induced expression of the transcription factor early growth response 1 (Egr-1) in neurons is tightly associated with many forms of neuronal activity, but the underlying target genes in the brain remained to be elucidated. This study uses a quantitative real-time PCR approach, in combination with invivo chromatin immunoprecipitation, and reveals that GABAA receptor subunit, GABRA2 (α2), GABRA4 (α4), and GABRQ (θ) genes, are transcriptional targets of Egr-1. Transfection of a construct that over-expresses Egr-1 in neuroblastoma (Neuro2A) cells up-regulates the α2, α4, and θ subunits. Given that Egr-1 knockout mice display less GABRA2, GABRA4, and GRBRQ mRNA in the hippocampus, and that Egr-1 directly binds to their promoters and induces mRNA expression, the present findings support a role for Egr-1 as a major regulator for altered GABAA receptor composition in homeostatic plasticity, in a glutamatergic activity-dependent manner. The early growth response 1 (Egr-1) is an inducible transcription factor to mediate rapid gene expression by neuronal activity. However, its underlying molecular target genes and mechanisms are not fully understood. We suggest that GABAA receptor subunits, GABRA2 (α2), GABRA4 (α4), and GABRQ (θ) genes are transcriptional targets of Egr-1. Neuronal activity-dependent up-regulation of Egr-1 might lead to altered subtypes of GABAA receptors for the maintenance of homeostatic excitatory and inhibitory balance for the regulation of synaptic strength.