Hartmann Jakob, Wagner Klaus V, Gaali Steffen, Kirschner Alexander, Kozany Christian, Rühter Gerd, Dedic Nina, Häusl Alexander S, Hoeijmakers Lianne, Westerholz Sören, Namendorf Christian, Gerlach Tamara, Uhr Manfred, Chen Alon, Deussing Jan M, Holsboer Florian, Hausch Felix, Schmidt Mathias V
Max Planck Institute of Psychiatry, 80804 Munich, Germany, and
Max Planck Institute of Psychiatry, 80804 Munich, Germany, and.
J Neurosci. 2015 Jun 17;35(24):9007-16. doi: 10.1523/JNEUROSCI.4024-14.2015.
Anxiety-related psychiatric disorders represent one of the largest health burdens worldwide. Single nucleotide polymorphisms of the FK506 binding protein 51 (FKBP51) gene have been repeatedly associated with anxiety-related disorders and stress sensitivity. Given the intimate relationship of stress and anxiety, we hypothesized that amygdala FKBP51 may mediate anxiety-related behaviors. Mimicking the stress effect by specifically overexpressing FKBP51 in the basolateral amygdala (BLA) or central amygdala resulted in increased anxiety-related behavior, respectively. In contrast, application of a highly selective FKBP51 point mutant antagonist, following FKBP51(mut) BLA-overexpression, reduced the anxiogenic phenotype. We subsequently tested a novel FKBP51 antagonist, SAFit2, in wild-type mice via BLA microinjections, which reduced anxiety-related behavior. Remarkably, the same effect was observed following peripheral administration of SAFit2. To our knowledge, this is the first in vivo study using a specific FKBP51 antagonist, thereby unraveling the role of FKBP51 and its potential as a novel drug target for the improved treatment of anxiety-related disorders.
焦虑相关的精神障碍是全球最大的健康负担之一。FK506结合蛋白51（FKBP51）基因的单核苷酸多态性 repeatedly 与焦虑相关障碍和应激敏感性有关。鉴于应激与焦虑的密切关系，我们推测杏仁核FKBP51可能介导焦虑相关行为。通过在基底外侧杏仁核（BLA）或中央杏仁核中特异性过表达FKBP51来模拟应激效应，分别导致焦虑相关行为增加。相比之下，在FKBP51（mut）BLA过表达后应用高度选择性的FKBP51点突变拮抗剂，可减轻致焦虑表型。我们随后通过BLA微量注射在野生型小鼠中测试了一种新型FKBP51拮抗剂SAFit2，它可减轻焦虑相关行为。值得注意的是，在SAFit2外周给药后也观察到了相同的效果。据我们所知，这是第一项使用特异性FKBP51拮抗剂的体内研究，从而揭示了FKBP51的作用及其作为改善焦虑相关障碍治疗的新型药物靶点的潜力。
