Increased EphA4-ephexin1 signaling in the medial prefrontal cortex plays a role in depression-like phenotype.
Increased EphA4-ephexin1 signaling in the medial prefrontal cortex plays a role in depression-like phenotype.
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DOI：
10.1038/s41598-017-07325-2
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发表时间：
2017-08-02
影响因子：
4.6
通讯作者：
Hashimoto K
中科院分区：
文献类型：
--
作者：
Zhang JC;Yao W;Qu Y;Nakamura M;Dong C;Yang C;Ren Q;Ma M;Han M;Shirayama Y;Hayashi-Takagi A;Hashimoto K
越来越多的证据表明，ephrin受体EphA4和下游蛋白epexin1在突触可塑性中起作用，这与抑郁症有关。我们研究了EphA4 - ephexin1信号是否在抑郁症的病理生理中起作用，以及EphA4抑制剂rhynchophilline的抗抑郁样作用。我们发现，在社交失败应激后，易感小鼠前额叶皮质（PFC）和海马中p-EphA4/EphA4和p-ephexin1/ephexin1的比值增加，而伏隔核（NAc）中p-EphA4/EphA4和p-ephexin1/ephexin1的比值没有增加。此外，抑郁症患者顶叶皮层p-EphA4/EphA4比值高于对照组。在社会失败应激模型中，通过抑制EphA4-ephexin1信号传导和激活PFC和海马中的脑源性神经营养因子- trkb信号传导，系统给药蛇尾碱产生了快速的抗抑郁样作用。在每次社会失败应激前用蛇尾碱预处理可预防多次社会失败应激后抑郁样表型的发生。EphA4腺相关病毒感染导致EphA4在内侧PFC过表达，3周后引起抑郁样表型，而蛇尾碱在这些小鼠中具有快速的抗抑郁样作用。这些发现表明PFC中EphA4-ephexin1信号的增加在抑郁症的病理生理中起作用。
Accumulating evidence suggests a role of the ephrin receptor EphA4 and the downstream protein ephexin1 in synaptic plasticity, which is implicated in depression. We examined whether EphA4–ephexin1 signaling plays a role in the pathophysiology of depression, and the antidepressant-like effect of EphA4 inhibitor rhynchophylline. We found increased ratios of p-EphA4/EphA4 and p-ephexin1/ephexin1 in the prefrontal cortex (PFC) and hippocampus but not in the nucleus accumbens (NAc), of susceptible mice after social defeat stress. Furthermore, the p-EphA4/EphA4 ratio was higher in the parietal cortex of depressed patients compared with controls. Systemic administration of rhynchophylline, produced a rapid antidepressant-like effect in a social defeat stress model by inhibiting EphA4–ephexin1 signaling and activating brain-derived neurotrophic factor-TrkB signaling in the PFC and hippocampus. Pretreatment with rhynchophylline before each social defeat stress could prevent the onset of the depression-like phenotype after repeated social defeat stress. Overexpression of EphA4 in the medial PFC owing to infection with an EphA4 adeno-associated virus caused the depression-like phenotype 3 weeks later and rhynchophylline had a rapid antidepressant-like effect in these mice. These findings suggest that increased EphA4–ephexin1 signaling in the PFC plays a role in the pathophysiology of depression.
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影响因子：
64.8
作者：
Hayashi-Takagi A;Yagishita S;Nakamura M;Shirai F;Wu YI;Loshbaugh AL;Kuhlman B;Hahn KM;Kasai H
通讯作者：
Kasai H
影响因子：
3.2
作者：
Fu, Amy K. Y.;Ip, Nancy Y.
通讯作者：
Ip, Nancy Y.
影响因子：
64.5
作者：
Dalva, MB;Takasu, MA;Greenberg, ME
通讯作者：
Greenberg, ME
影响因子：
4.7
作者：
Bouvier, David;Corera, Amadou T.;Doucet, Guy
通讯作者：
Doucet, Guy
影响因子：
5
作者：
Kang, TH;Murakami, Y;Watanabe, H
通讯作者：
Watanabe, H