The Immediate Early Gene Egr3 Is Required for Hippocampal Induction of Bdnf by Electroconvulsive Stimulation.
The Immediate Early Gene Egr3 Is Required for Hippocampal Induction of Bdnf by Electroconvulsive Stimulation.
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DOI：
10.3389/fnbeh.2018.00092
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发表时间：
2018
影响因子：
3
通讯作者：
Gallitano AL
中科院分区：
文献类型：
--
作者：
Meyers KT;Marballi KK;Brunwasser SJ;Renda B;Charbel M;Marrone DF;Gallitano AL
早期生长反应3 （Egr3）是一种即时早期基因（IEG），受一系列与精神疾病风险相关的基因的下游调控，Egr3本身的功能障碍与精神分裂症、双相情感障碍和抑郁症有关。作为一种活性依赖性转录因子，EGR3可以调节目标基因的神经元表达以应对环境事件。在目前的研究中，我们试图确定EGR3的下游靶点，目的是进一步阐明这一生物学途径中与精神疾病风险相关的基因。我们使用电惊厥刺激（ECS）在大脑中诱导高水平表达eggs，并使用表达微阵列来鉴定与野生型（WT）小鼠相比，egr3缺陷（-/-）小鼠海马中差异调节的基因。我们的研究结果重复了之前的工作，表明ECS诱导WT小鼠海马中脑源性神经营养因子（Bdnf）的高水平表达。然而，我们发现这种诱导在Egr3-/-小鼠中不存在。定量实时PCR （qRT-PCR）验证了微阵列结果（在雄性小鼠中进行），并在两个单独的雌性小鼠队列中重复了这一发现。对活性依赖性Bdnf外显子的后续研究表明，ecs诱导的外显子IV和VI的表达都需要Egr3。原位杂交显示，在WT小鼠的ECS后，海马齿状回中Bdnf的细胞表达水平较高，而Egr3-/-小鼠则没有。Bdnf启动子分析揭示了Bdnf启动子中8个可能的EGR3结合位点，提示EGR3可能通过其直接调控Bdnf基因表达的机制。这些发现似乎不是由Egr3-/-小鼠海马神经元发育缺陷引起的，因为用抗neun抗体（一种神经元特异性标记物）染色的组织切片中的细胞计数在Egr3-/-和WT小鼠之间没有差异。此外，高尔基染色海马切片的Sholl分析和树突棘计数显示，与WT相比，Egr3-/-小鼠的树突形态和突触棘密度没有差异。这些发现表明Egr3是ecs诱导的海马中Bdnf表达所必需的，并表明Bdnf可能是我们之前确定的精神疾病易感性生物学途径的下游基因。
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.
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DOI：
10.1002/syn.21900
发表时间：
2016-07
期刊：
Synapse (New York, N.Y.)
影响因子：
--
作者：
Gallitano AL;Satvat E;Gil M;Marrone DF
通讯作者：
Marrone DF
DOI：
10.1016/j.pbb.2010.11.009
发表时间：
2011-08
期刊：
Pharmacology, biochemistry, and behavior
影响因子：
--
作者：
Goff DC;Hill M;Barch D
通讯作者：
Barch D
影响因子：
3.5
作者：
Chiaruttini, C.;Sonego, M.;Tongiorgi, E.
通讯作者：
Tongiorgi, E.
影响因子：
--
作者：
ABERCROMBIE, M
通讯作者：
ABERCROMBIE, M
影响因子：
5.6
作者：
Bocchio-Chiavetto, Luisella;Zanardini, Roberta;Gennarelli, Massimo
通讯作者：
Gennarelli, Massimo