Schmidt Ulrike, Buell Dominik R, Ionescu Irina A, Gassen Nils C, Holsboer Florian, Cox Marc B, Novak Bozidar, Huber Christine, Hartmann Jakob, Schmidt Mathias V, Touma Chadi, Rein Theo, Herrmann Leonie
Max Planck Institute of Psychiatry, Department of Clinical Research, RG Molecular Psychotraumatology, Munich, Germany.
Max Planck Institute of Psychiatry, Department of Clinical Research, RG Molecular Psychotraumatology, Munich, Germany.
Psychoneuroendocrinology. 2015 Feb;52:43-58. doi: 10.1016/j.psyneuen.2014.11.005. Epub 2014 Nov 11.
Both the molecular co-chaperone FKBP51 and the presynaptic vesicle protein synapsin (alternatively spliced from SYN1-3) are intensively discussed players in the still insufficiently explored pathobiology of psychiatric disorders such as major depression, schizophrenia and posttraumatic stress disorder (PTSD). To address their still unknown interaction, we compared the expression levels of synapsin and five other neurostructural and HPA axis related marker proteins in the prefrontal cortex (PFC) and the hippocampus of restrained-stressed and unstressed Fkbp5 knockout mice and corresponding wild-type littermates. In addition, we compared and correlated the gene expression levels of SYN1, SYN2 and FKBP5 in three different online datasets comprising expression data of human healthy subjects as well as of predominantly medicated patients with different psychiatric disorders. In summary, we found that Fkbp5 deletion, which we previously demonstrated to improve stress-coping behavior in mice, prevents the stress-induced decline in prefrontal cortical (pc), but not in hippocampal synapsin expression. Accordingly, pc, but not hippocampal, synapsin protein levels correlated positively with a more active mouse stress coping behavior. Searching for an underlying mechanism, we found evidence that deletion of Fkbp5 might prevent stress-induced pc synapsin loss, at least in part, through improvement of pc Akt kinase activity. These results, together with our finding that FKBP5 and SYN1 mRNA levels were regulated in opposite directions in the PFC of schizophrenic patients, who are known for exhibiting an altered stress-coping behavior, provide the first evidence of a role for pc synapsin in FKBP51 modulation of stress responsiveness. This role might extend to other tissues, as we found FKBP5 and SYN1 levels to correlate inversely not only in human PFC samples but also in other expression sites. The main limitation of this study is the small number of individuals included in the correlation analyses. Future studies will have to verify the here-postulated role of the FKBP51-Akt kinase-synapsin pathway in stress responsiveness.
分子伴侣FKBP51和突触前囊泡蛋白突触素（由SYN1 - 3可变剪接而成）都是在诸如重度抑郁症、精神分裂症和创伤后应激障碍（PTSD）等尚未得到充分研究的精神疾病病理生物学中被广泛讨论的因素。为了探究它们仍不为人知的相互作用，我们比较了Fkbp5基因敲除小鼠和相应野生型同窝小鼠在受到束缚应激和未受应激状态下前额叶皮质（PFC）和海马体中突触素以及其他五种与神经结构和HPA轴相关的标记蛋白的表达水平。此外，我们还比较并关联了SYN1、SYN2和FKBP5在三个不同在线数据集中的基因表达水平，这些数据集包含人类健康受试者以及主要为患有不同精神疾病的服药患者的表达数据。总之，我们发现Fkbp5基因缺失（我们之前证明其可改善小鼠的应激应对行为）可防止应激诱导的前额叶皮质（pc）中突触素表达下降，但不能防止海马体中突触素表达下降。相应地，pc而非海马体中的突触素蛋白水平与小鼠更积极的应激应对行为呈正相关。在寻找潜在机制时，我们发现有证据表明Fkbp5基因缺失可能至少部分通过改善pc Akt激酶活性来防止应激诱导的pc突触素丢失。这些结果，连同我们发现FKBP5和SYN1 mRNA水平在以应激应对行为改变而闻名的精神分裂症患者的PFC中呈相反方向调节，首次证明了pc突触素在FKBP51调节应激反应性中的作用。这一作用可能扩展到其他组织，因为我们发现FKBP5和SYN1水平不仅在人类PFC样本中呈负相关，在其他表达位点也是如此。本研究的主要局限性在于相关性分析中纳入的个体数量较少。未来的研究将必须验证这里所假设的FKBP51 - Akt激酶 - 突触素途径在应激反应性中的作用。
