Vesicular monoamine transporter 2 mediates fear behavior in mice.
Vesicular monoamine transporter 2 mediates fear behavior in mice.
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DOI：
10.1111/gbb.12634
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发表时间：
2020-06
期刊：
影响因子：
--
通讯作者：
Miller GW
中科院分区：
文献类型：
--
作者：
Branco RC;Burkett JP;Black CA;Winokur E;Ellsworth W;Dhamsania RK;Lohr KM;Schroeder JP;Weinshenker D;Jovanovic T;Miller GW
经历过创伤事件的一部分人会出现创伤后应激障碍（PTSD），这与失调的恐惧行为有关。据报道，编码囊泡单胺转运蛋白 2 (VMAT2) 的基因 SLC18A2 的遗传变异会影响人类发生 PTSD 的风险。在这里，我们使用表达野生型 VMAT2 蛋白水平 5%（VMAT2-LO 小鼠）或 200%（VMAT2-HI 小鼠）的转基因小鼠。我们报告VMAT2-LO小鼠海马和杏仁核中的VMAT2蛋白减少，纹状体和额叶皮质中的单胺能囊泡储存能力受损，单胺代谢丰度降低，并且在刺激时释放多巴胺的能力大大降低。此外，VMAT2-LO小鼠表现出夸大的提示和情境恐惧表达、改变的恐惧习惯、无法区分威胁和安全提示、与野生型小鼠相比惊吓反应改变以及类似焦虑的表型，但没有表现出社交功能缺陷。相比之下，与野生型对照相比，VMAT2-HI 小鼠的整个大脑中的 VMAT2 蛋白增加，囊泡储存容量更高，刺激后多巴胺释放更多。在行为上，VMAT2-HI 小鼠在大多数检测中与野生型小鼠相似，有一些证据表明焦虑样反应减少。总之，这些数据表明，在我们的小鼠模型中，突触前单胺功能介导类似 PTSD 的结果，并表明 VMAT2 表达减少和恐惧行为之间存在因果关系，这与人类 VMAT2 基因型和 PTSD 风险之间的相关关系一致。针对这一系统是开发针对创伤后应激障碍（PTSD）等疾病的药物疗法的潜在策略。
A subset of people exposed to a traumatic event develop post-traumatic stress disorder (PTSD), which is associated with dysregulated fear behavior. Genetic variation in SLC18A2, the gene that encodes vesicular monoamine transporter 2 (VMAT2), has been reported to affect risk for the development of PTSD in humans. Here, we use transgenic mice that express either 5% (VMAT2-LO mice) or 200% (VMAT2-HI mice) of wild-type levels of VMAT2 protein. We report that VMAT2-LO mice have reduced VMAT2 protein in the hippocampus and amygdala, impaired monoaminergic vesicular storage capacity in both the striatum and frontal cortex, decreased monoamine metabolite abundance, and a greatly reduced capacity to release dopamine upon stimulation. Furthermore, VMAT2-LO mice showed exaggerated cued and contextual fear expression, altered fear habituation, inability to discriminate threat from safety cues, altered startle response compared to wild-type mice, and an anxiogenic-like phenotype, but displayed no deficits in social function. By contrast, VMAT2-HI mice exhibited increased VMAT2 protein throughout the brain, higher vesicular storage capacity, and greater dopamine release upon stimulation compared to wild-type controls. Behaviorally, VMAT2-HI mice were similar to wild-type mice in most assays, with some evidence of a reduced anxiety-like responses. Together, these data demonstrate that presynaptic monoamine function mediates PTSD-like outcomes in our mouse model, and suggest a causal link between reduced VMAT2 expression and fear behavior, consistent with the correlational relationship between VMAT2 genotype and PTSD risk in humans. Targeting this system is a potential strategy for the development of pharmacotherapies for disorders like PTSD.
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影响因子：
3.7
作者：
Flandreau, Elizabeth;Risbrough, Victoria;Lu, Ailing;Ableitner, Martin;Geyer, Mark A.;Holsboer, Florian;Deussing, Jan M.
通讯作者：
Deussing, Jan M.
影响因子：
4.7
作者：
Jovanovic T;Kazama A;Bachevalier J;Davis M
通讯作者：
Davis M
影响因子：
7.4
作者：
Glover, Ebony M.;Phifer, Justine E.;Crain, Daniel F.;Norrholm, Seth D.;Davis, Michael;Bradley, Bekh;Ressler, Kerry J.;Jovanovic, Tanja
通讯作者：
Jovanovic, Tanja
影响因子：
5.2
作者：
Eiden LE;Weihe E
通讯作者：
Weihe E
影响因子：
--
作者：
KESSLER, RC;SONNEGA, A;NELSON, CB
通讯作者：
NELSON, CB