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The stress susceptibility factor FKBP51 controls S-ketamine-evoked release of mBDNF in the prefrontal cortex of mice
Neurobiology of Stress ( IF 4.3 ) Pub Date : 2020-07-04 , DOI: 10.1016/j.ynstr.2020.100239
Elmira Anderzhanova , Kathrin Hafner , Andreas J. Genewsky , Azza Soliman , Max L. Pöhlmann , Mathias V. Schmidt , Robert Blum , Carsten T. Wotjak , Nils C. Gassen

We report here the involvement of the stress-responsive glucocorticoid receptor co-chaperone FKBP51 in the mechanism of in vivo secretion of mature BDNF (mBDNF). We used a novel method combining brain microdialysis with a capillary electrophoresis-based immunoassay, to examine mBDNF secretion in the medial prefrontal cortex (mPFC) in vivo in freely moving mice. By combining optogenetic, neurochemical (KCl-evoked depolarization), and transgenic (conditional BDNF knockout mice) means, we have shown that the increase in extracellular mBDNF in vivo is determined by neuronal activity. Withal, mBDNF secretion in the mPFC of mice was stimulated by a systemic administration of S-ketamine (10 or 50 mg/kg) or S-hydroxynorketamine (10 mg/kg).

KCl- and S-ketamine-evoked mBDNF secretion was strongly dependent on the expression of FKBP51. Moreover, the inability of S-ketamine to evoke a transient secretion in mBDNF in the mPFC in FKBP51- knockout mice matched the lack of antidepressant-like effect of S-ketamine in the tail suspension test. Our data reveal a critical role of FKBP51 in mBDNF secretion and suggest the involvement of mBDNF in the realization of immediate stress-coping behavior induced by acute S-ketamine.



中文翻译:

应激敏感性因子FKBP51控制S-氯胺酮引起的小鼠前额叶皮层中mBDNF的释放

我们在这里报告的应激反应的糖皮质激素受体伴侣分子FKBP51参与成熟的BDNF(mBDNF)内分泌的机制。我们使用一种新颖的方法,将脑微透析与基于毛细管电泳的免疫测定相结合,以检查自由移动小鼠体内前额叶皮层(mPFC)中的mBDNF分泌。通过结合光遗传学,神经化学(KCl引起的去极化)和转基因(条件性BDNF敲除小鼠)手段,我们已经表明体内细胞外mBDNF的增加是由神经元活性决定的。通过全身性施用S-氯胺酮(10或50mg / kg)或S-羟基降甲胺酮(10mg / kg)刺激小鼠mPFC中的mBDNF分泌。

KCl和S-氯胺酮引起的mBDNF分泌强烈依赖于FKBP51的表达。此外,S-氯胺酮不能引起FKBP51基因敲除小鼠的mPFC中mBDFC中mBDNF的瞬时分泌,这与尾部悬吊试验中S-氯胺酮的抗抑郁样作用缺乏有关。我们的数据揭示了FKBP51在mBDNF分泌中的关键作用,并暗示mBDNF参与了由急性S-氯胺酮诱导的即时应激应对行为的实现。

更新日期:2020-07-04
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