Phenotypic characterization of transgenic mice overexpressing neuregulin-1.
Phenotypic characterization of transgenic mice overexpressing neuregulin-1.
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DOI：
10.1371/journal.pone.0014185
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发表时间：
2010-12-09
期刊：
影响因子：
3.7
通讯作者：
Nawa H
中科院分区：
文献类型：
--
作者：
Kato T;Kasai A;Mizuno M;Fengyi L;Shintani N;Maeda S;Yokoyama M;Ozaki M;Nawa H
Neuregulin-1 (NRG1) 是精神分裂症的易感基因之一，参与 GABA 能和多巴胺能神经元、髓鞘形成和 NMDA 受体功能的神经营养调节。尸检研究通常表明 NRG1 表达或信号传导增加与这种疾病存在病理关联。然而，NRG1 信号传导的心理行为影响主要是使用亚等位突变小鼠的个体 NRG1 剪接变体进行研究。为了评估 hyper NRG1 信号传导的行为影响，我们生成并分析了两个独立的小鼠转基因 (Tg) 系，其携带绿色荧光蛋白 (GFP) 标记的 1 型 NRG1 cDNA 转基因。延伸因子 1α 基因的启动子驱动 GFP 标记的 NRG1 在整个大脑中普遍表达。与对照同窝小鼠相比，两个杂合的 NRG1-Tg 系均表现出运动活性增加、前脉冲抑制减少的非显着趋势以及情境依赖性恐惧学习的减少，但表现出音调依赖性学习的正常水平。此外，在隔离引起的居民-入侵者测试中，两条 Tg 系的社交互动得分均有所下降。尽管海马中的酪氨酸羟化酶水平和多巴胺含量显着降低，但额叶皮质中的 GABA 能标记物（小清蛋白）和髓鞘形成标记物（髓磷脂碱性蛋白和 2',3'-环核苷酸 3'-磷酸二酯酶）也出现表型增加，表明 NRG1 超信号传导的真实性。这些发现表明 NRG1 的异常超信号还会扰乱各种认知和行为过程。因此，应通过进一步的实验来评估高 NRG1 信号传导在精神疾病中的神经病理学意义。
Neuregulin-1 (NRG1) is one of the susceptibility genes for schizophrenia and implicated in the neurotrophic regulation of GABAergic and dopaminergic neurons, myelination, and NMDA receptor function. Postmortem studies often indicate a pathologic association of increased NRG1 expression or signaling with this illness. However, the psychobehavioral implication of NRG1 signaling has mainly been investigated using hypomorphic mutant mice for individual NRG1 splice variants. To assess the behavioral impact of hyper NRG1 signaling, we generated and analyzed two independent mouse transgenic (Tg) lines carrying the transgene of green fluorescent protein (GFP)-tagged type-1 NRG1 cDNA. The promoter of elongation-factor 1α gene drove ubiquitous expression of GFP-tagged NRG1 in the whole brain. As compared to control littermates, both heterozygous NRG1-Tg lines showed increased locomotor activity, a nonsignificant trend toward decreasing prepulse inhibition, and decreased context-dependent fear learning but exhibited normal levels of tone-dependent learning. In addition, social interaction scores in both Tg lines were reduced in an isolation-induced resident-intruder test. There were also phenotypic increases in a GABAergic marker (parvalbumin) as well as in myelination markers (myelin basic protein and 2′,3′-cyclic nucleotide 3′-phosphodiesterase) in their frontal cortex, indicating the authenticity of NRG1 hyper-signaling, although there were marked decreases in tyrosine hydroxylase levels and dopamine content in the hippocampus. These findings suggest that aberrant hyper-signals of NRG1 also disrupt various cognitive and behavioral processes. Thus, neuropathological implication of hyper NRG1 signaling in psychiatric diseases should be evaluated with further experimentation.
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DOI：
10.1523/jneurosci.1815-08.2008
发表时间：
2008-07-02
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Chen YJ;Johnson MA;Lieberman MD;Goodchild RE;Schobel S;Lewandowski N;Rosoklija G;Liu RC;Gingrich JA;Small S;Moore H;Dwork AJ;Talmage DA;Role LW
通讯作者：
Role LW
影响因子：
16.2
作者：
Brinkmann, Bastian G.;Agarwal, Amit;Sereda, Michael W.;Garratt, Alistair N.;Mueller, Thomas;Wende, Hagen;Stassart, Ruth M.;Nawaz, Schanila;Humml, Christian;Velanac, Viktorija;Radyushkin, Konstantin;Goebbels, Sandra;Fischer, Tobias M.;Franklin, Robin J.;Lai, Cary;Ehrenreich, Hannelore;Birchmeier, Carmen;Schwab, Markus H.;Nave, Klaus Armin
通讯作者：
Nave, Klaus Armin
影响因子：
3.5
作者：
Frankland, PW;Josselyn, A;Silva, AJ
通讯作者：
Silva, AJ
影响因子：
3.5
作者：
Li, Dawei;Collier, David A.;He, Lin
通讯作者：
He, Lin
影响因子：
16.2
作者：
Flames, N;Long, JE;Marín, O
通讯作者：
Marín, O