Microglial ERK-NRBP1-CREB-BDNF signaling in sustained antidepressant actions of (R)-ketamine.
Microglial ERK-NRBP1-CREB-BDNF signaling in sustained antidepressant actions of (R)-ketamine.
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DOI：
10.1038/s41380-021-01377-7
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发表时间：
2022-03
影响因子：
11
通讯作者：
Zhang, Ji-Chun
中科院分区：
文献类型：
--
作者：
Yao, Wei;Cao, Qianqian;Luo, Shilin;He, Lujuan;Yang, Chun;Chen, Jiaxu;Qi, Qi;Hashimoto, Kenji;Zhang, Ji-Chun
（R，S）-氯胺酮在难治性抑郁症患者中具有速效和持续的抗抑郁作用。在啮齿动物中，（R）-氯胺酮产生的抗抑郁作用比（S）-氯胺酮持久;然而，（R）-氯胺酮抗抑郁作用的确切分子机制仍未知。使用同量异序标签的相对和绝对定量，我们确定了核受体结合蛋白1（NRBP 1），可能有助于不同的抗抑郁样作用的两种对映体在慢性社会失败应激（CSDS）模型。NRBP 1定位于小鼠内侧前额叶皮质（mPFC）的小胶质细胞和神经元，而不是星形胶质细胞。（R）-氯胺酮通过细胞外信号调节激酶（ERK）激活增加原代小胶质细胞培养物中NRBP 1、脑源性神经营养因子（BDNF）和磷酸化cAMP反应元件结合蛋白（p-CREB）/CREB比率的表达。此外，（R）-氯胺酮可通过激活CREB以及抑制小胶质细胞中的MeCP 2（甲基-CpG结合蛋白2）来激活BDNF转录。单次侧脑室注射（i. c. v.）注射CREB-DNA/RNA异源双链寡核苷酸（CREB-HDO）或BDNF外显子IV-HDO阻断了（R）-氯胺酮在CSDS易感小鼠中的抗抑郁样作用。此外，通过集落刺激因子1受体（CSF 1 R）抑制剂PLX 3397消除小胶质细胞可阻断CSDS易感小鼠中（R）-氯胺酮的抗抑郁样作用。此外，通过单次i. c. v.注射甘露糖基氯膦酸盐脂质体（MCL）抑制小胶质细胞可显著阻断CSDS易感小鼠中（R）-氯胺酮的抗抑郁样作用。最后，单次i. c. v.注射CREB-HDO、BDNF外显子IV-HDO或MCL阻断了（R）-氯胺酮对CSDS易感小鼠mPFC中树突棘密度降低的有益作用。这些数据表明，小胶质细胞中的一种新的ERK-NRBP 1-CREB-BDNF通路是（R）-氯胺酮抗抑郁样作用的基础。
(R,S)-ketamine elicits rapid-acting and sustained antidepressant actions in treatment-resistant patients with depression. (R)-ketamine produces longer-lasting antidepressant effects than (S)-ketamine in rodents; however, the precise molecular mechanisms underlying antidepressant actions of (R)-ketamine remain unknown. Using isobaric Tag for Relative and Absolute Quantification, we identified nuclear receptor-binding protein 1 (NRBP1) that could contribute to different antidepressant-like effects of the two enantiomers in chronic social defeat stress (CSDS) model. NRBP1 was localized in the microglia and neuron, not astrocyte, of mouse medial prefrontal cortex (mPFC). (R)-ketamine increased the expression of NRBP1, brain-derived neurotrophic factor (BDNF), and phosphorylated cAMP response element binding protein (p-CREB)/CREB ratio in primary microglia cultures thorough the extracellular signal-regulated kinase (ERK) activation. Furthermore, (R)-ketamine could activate BDNF transcription through activation of CREB as well as MeCP2 (methyl-CpG binding protein 2) suppression in microglia. Single intracerebroventricular (i.c.v.) injection of CREB-DNA/RNA heteroduplex oligonucleotides (CREB-HDO) or BDNF exon IV-HDO blocked the antidepressant-like effects of (R)-ketamine in CSDS susceptible mice. Moreover, microglial depletion by colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX3397 blocked the antidepressant-like effects of (R)-ketamine in CSDS susceptible mice. In addition, inhibition of microglia by single i.c.v. injection of mannosylated clodronate liposomes (MCLs) significantly blocked the antidepressant-like effects of (R)-ketamine in CSDS susceptible mice. Finally, single i.c.v. injection of CREB-HDO, BDNF exon IV-HDO or MCLs blocked the beneficial effects of (R)-ketamine on the reduced dendritic spine density in the mPFC of CSDS susceptible mice. These data suggest a novel ERK-NRBP1-CREB-BDNF pathways in microglia underlying antidepressant-like effects of (R)-ketamine.
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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：两个对映异构体的故事。
DOI：
10.1177/0269881120959644
发表时间：
2021-03
期刊：
Journal of psychopharmacology (Oxford, England)
影响因子：
--
作者：
Jelen LA;Young AH;Stone JM
通讯作者：
Stone JM
影响因子：
11
作者：
Fava M;Freeman MP;Flynn M;Judge H;Hoeppner BB;Cusin C;Ionescu DF;Mathew SJ;Chang LC;Iosifescu DV;Murrough J;Debattista C;Schatzberg AF;Trivedi MH;Jha MK;Sanacora G;Wilkinson ST;Papakostas GI
通讯作者：
Papakostas GI
影响因子：
5
作者：
Ebert, B;Mikkelsen, S;Borgbjerg, FM
通讯作者：
Borgbjerg, FM
影响因子：
16.2
作者：
Chang, QA;Khare, G;Jaenisch, R
通讯作者：
Jaenisch, R