The Immediate Early Gene Egr3 Is Required for Hippocampal Induction of Bdnf by Electroconvulsive Stimulation
AuthorMeyers, Kimberly T.
Marballi, Ketan K.
Brunwasser, Samuel J.
Marrone, Diano F.
Gallitano, Amelia L.
AffiliationUniv Arizona, Coll Med Phoenix, Dept Basic Med Sci
Univ Arizona, Evelyn F McKnight Brain Inst
immediate early genes
early growth response 3
brain-derived neurotrophic factor
MetadataShow full item record
PublisherFRONTIERS MEDIA SA
CitationMeyers KT, Marballi KK, Brunwasser SJ, Renda B, Charbel M, Marrone DF and Gallitano AL (2018) The Immediate Early Gene Egr3 Is Required for Hippocampal Induction of Bdnf by Electroconvulsive Stimulation. Front. Behav. Neurosci. 12:92. doi: 10.3389/fnbeh.2018.00092
Rights© 2018 Meyers, Marballi, Brunwasser, Renda, Charbel, Marrone and Gallitano. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).
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AbstractEarly 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.
NoteOpen access journal.
VersionFinal published version
SponsorsUS National Institute of Mental Health [R01MH097803, R21MH113154]; Natural Sciences and Engineering Research Council of Canada
Except where otherwise noted, this item's license is described as © 2018 Meyers, Marballi, Brunwasser, Renda, Charbel, Marrone and Gallitano. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).