Involvement of the agmatinergic system in the depressive-like phenotype of the Crtc1 knockout mouse model of depression.
Involvement of the agmatinergic system in the depressive-like phenotype of the Crtc1 knockout mouse model of depression.
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DOI：
10.1038/tp.2016.116
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发表时间：
2016-07-12
影响因子：
6.8
通讯作者：
Cardinaux JR
中科院分区：
文献类型：
--
作者：
Meylan EM;Breuillaud L;Seredenina T;Magistretti PJ;Halfon O;Luthi-Carter R;Cardinaux JR
最近的研究表明精氨酸脱羧产物胍丁胺具有情绪调节作用。胍丁胺在抑郁症啮齿动物模型中具有抗抑郁作用，而胍丁胺酶 (Agmat)（一种胍丁胺降解酶）在情绪障碍患者的大脑中表达上调。我们之前已经证明，缺乏 CREB 调节的转录共激活因子 1 (CRTC1) 的小鼠与行为和分子抑郁样内表型相关，并且对经典抗抑郁药的反应减弱。在这里，使用微阵列基因表达谱进一步检查了 Crtc1−/− 小鼠行为表型的分子基础，结果揭示了 Crtc1−/− 小鼠皮质中 Agmat 的上调。定量聚合酶链反应和蛋白质印迹分析证实 Crtc1−/− 前额皮质 (PFC) 和海马中 Agmat 上调，共聚焦免疫荧光显微镜进一步证明 Agmat 表达细胞数量增加，特别是小白蛋白和生长抑素阳性中间神经元。在强迫游泳测试中，急性胍丁胺和氯胺酮治疗可显着改善雄性和雌性 Crtc1−/− 小鼠的抑郁样行为，表明外源性胍丁胺通过补偿因 Agmat 上调而导致的胍丁胺缺陷，从而具有快速抗抑郁作用。胍丁胺仅在野生型（WT）雌性小鼠的 PFC 中快速增加脑源性神经营养因子（BDNF）水平，并降低雄性和雌性 WT 小鼠 PFC 中的真核延伸因子 2（eEF2）磷酸化，表明胍丁胺可能是一种具有 N-甲基-D-天冬氨酸（NMDA）受体拮抗剂特性的速效抗抑郁药。总的来说，这些发现表明 Agmat 与 Crtc1−/− 小鼠的抑郁样表型有关，完善了目前对大脑中 Agmatinergic 系统的理解，并强调了其在重度抑郁症中的假定作用。
Recent studies implicate the arginine-decarboxylation product agmatine in mood regulation. Agmatine has antidepressant properties in rodent models of depression, and agmatinase (Agmat), the agmatine-degrading enzyme, is upregulated in the brains of mood disorder patients. We have previously shown that mice lacking CREB-regulated transcription coactivator 1 (CRTC1) associate behavioral and molecular depressive-like endophenotypes, as well as blunted responses to classical antidepressants. Here, the molecular basis of the behavioral phenotype of Crtc1−/− mice was further examined using microarray gene expression profiling that revealed an upregulation of Agmat in the cortex of Crtc1−/− mice. Quantitative polymerase chain reaction and western blot analyses confirmed Agmat upregulation in the Crtc1−/− prefrontal cortex (PFC) and hippocampus, which were further demonstrated by confocal immunofluorescence microscopy to comprise an increased number of Agmat-expressing cells, notably parvalbumin- and somatostatin-positive interneurons. Acute agmatine and ketamine treatments comparably improved the depressive-like behavior of male and female Crtc1−/− mice in the forced swim test, suggesting that exogenous agmatine has a rapid antidepressant effect through the compensation of agmatine deficit because of upregulated Agmat. Agmatine rapidly increased brain-derived neurotrophic factor (BDNF) levels only in the PFC of wild-type (WT) females, and decreased eukaryotic elongation factor 2 (eEF2) phosphorylation in the PFC of male and female WT mice, indicating that agmatine might be a fast-acting antidepressant with N-methyl-D-aspartate (NMDA) receptor antagonist properties. Collectively, these findings implicate Agmat in the depressive-like phenotype of Crtc1−/− mice, refine current understanding of the agmatinergic system in the brain and highlight its putative role in major depression.
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影响因子：
10.6
作者：
Autry, Anita E.;Adachi, Megumi;Cheng, Pengfei;Monteggia, Lisa M.
通讯作者：
Monteggia, Lisa M.
影响因子：
64.8
作者：
Autry, Anita E.;Adachi, Megunai;Nosyreva, Elena;Na, Elisa S.;Los, Maarten F.;Cheng, Peng-fei;Kavalali, Ege T.;Monteggia, Lisa M.
通讯作者：
Monteggia, Lisa M.
氯胺酮和快速作用的抗抑郁药：介绍新的神经生物学的窗口，用于情绪障碍疗法。
影响因子：
10.5
作者：
Abdallah CG;Sanacora G;Duman RS;Krystal JH
通讯作者：
Krystal JH
DOI：
10.1126/science.1190287
发表时间：
2010-08-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Li N;Lee B;Liu RJ;Banasr M;Dwyer JM;Iwata M;Li XY;Aghajanian G;Duman RS
通讯作者：
Duman RS
影响因子：
4.7
作者：
Meylan EM;Halfon O;Magistretti PJ;Cardinaux JR
通讯作者：
Cardinaux JR