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Early growth response 3 ( Egr3 ) is an immediate early gene (IEG) that is regulated downstream of a cascade of genes associated with risk for psychiatric disorders, and dysfunction of  Egr3  itself has been implicated in schizophrenia, bipolar disorder, and depression. As an activity-dependent transcription factor, EGR3 is poised to regulate the neuronal expression of target genes in response to environmental events. In the current study, we sought to identify a downstream target of EGR3 with the goal of further elucidating genes in this biological pathway relevant for psychiatric illness risk. We used electroconvulsive stimulation (ECS) to induce high-level expression of IEGs in the brain, and conducted expression microarray to identify genes differentially regulated in the hippocampus of Egr3-deficient (-/-) mice compared to their wildtype (WT) littermates. Our results replicated previous work showing that ECS induces high-level expression of the brain-derived neurotrophic factor ( Bdnf ) in the hippocampus of WT mice. However, we found that this induction is absent in  Egr3 -/- mice. Quantitative real-time PCR (qRT-PCR) validated the microarray results (performed in males) and replicated the findings in two separate cohorts of female mice. Follow-up studies of activity-dependent  Bdnf  exons demonstrated that ECS-induced expression of both exons IV and VI requires  Egr3 .  In situ  hybridization demonstrated high-level cellular expression of  Bdnf  in the hippocampal dentate gyrus following ECS in WT, but not  Egr3 -/-, mice.  Bdnf  promoter analysis revealed eight putative EGR3 binding sites in the  Bdnf  promoter, suggesting a mechanism through which EGR3 may directly regulate  Bdnf  gene expression. These findings do not appear to result from a defect in the development of hippocampal neurons in  Egr3 -/- mice, as cell counts in tissue sections stained with anti-NeuN antibodies, a neuron-specific marker, did not differ between  Egr3 -/- and WT mice. In addition, Sholl analysis and counts of dendritic spines in golgi-stained hippocampal sections revealed no difference in dendritic morphology or synaptic spine density in  Egr3 -/-, compared to WT, mice. These findings indicate that  Egr3  is required for ECS-induced expression of  Bdnf  in the hippocampus and suggest that  Bdnf  may be a downstream gene in our previously identified biologically pathway for psychiatric illness susceptibility.

The Immediate Early Gene Egr3 Is Required for Hippocampal Induction of Bdnf by Electroconvulsive Stimulation