Nuclear factor of activated T cells 4 in the prefrontal cortex is required for prophylactic actions of (R)-ketamine.
Nuclear factor of activated T cells 4 in the prefrontal cortex is required for prophylactic actions of (R)-ketamine.
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DOI：
10.1038/s41398-022-01803-6
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发表时间：
2022-01-21
影响因子：
6.8
通讯作者：
Hashimoto K
中科院分区：
文献类型：
--
作者：
Ma L;Zhang J;Fujita Y;Qu Y;Shan J;Wan X;Wang X;Ishima T;Kobayashi K;Wang L;Hashimoto K
(R，S)-氯胺酮在啮齿动物中具有预防性抗抑郁药样作用；然而，其作用的确切分子机制尚不清楚。通过测序分析，我们找到了与(R)-氯胺酮更强的对映体(R，S)-氯胺酮预防作用有关的新的分子靶点(S)。(R)-氯胺酮(10 mg/kg，前6天)可显著改善脂多糖(LPS：1.0 mg/kg)诱导的小鼠体重减轻、脾肿大和强迫游泳不动时间延长。前额叶皮质(PFC)和随后的IPA(独创性通路分析)的RNA测序分析表明，激活的T细胞核因子4(NFATc4)信号可能参与了(R)-氯胺酮的持续预防作用。定量RT-PCR证实，(R)-氯胺酮显著抑制内毒素诱导的小鼠PFC中NFATc4信号(NFATc4、CD4、CD79B、H2-AB1、H2-AA)基因表达的增加。此外，预先给予NFAT抑制剂(即NFAT抑制剂和环孢素A)对脂多糖处理的小鼠有预防作用。与(R)-氯胺酮类似，双侧腺相关病毒(AAV)基因敲除mPFC中的NFATC4基因可引起内毒素处理的小鼠的预防作用。综上所述，我们的数据暗示在PFC中存在一条新的NFATc4信号通路，其基础是(R)-氯胺酮对炎症相关抑郁的预防作用。
(R, S)-ketamine has prophylactic antidepressant-like effects in rodents; however, the precise molecular mechanisms underlying its action remain unknown. Using RNA-sequencing analysis, we searched novel molecular target(s) that contribute to the prophylactic effects of (R)-ketamine, a more potent enantiomer of (R, S)-ketamine. Pretreatment with (R)-ketamine (10 mg/kg, 6 days before) significantly ameliorated body weight loss, splenomegaly, and increased immobility time of forced swimming test in lipopolysaccharide (LPS: 1.0 mg/kg)-treated mice. RNA-sequencing analysis of prefrontal cortex (PFC) and subsequent IPA (Ingenuity Pathway Analysis) revealed that the nuclear factor of activated T cells 4 (NFATc4) signaling might contribute to sustained prophylactic effects of (R)-ketamine. Quantitative RT-PCR confirmed that (R)-ketamine significantly attenuated the increased gene expression of NFATc4 signaling (Nfatc4, Cd4, Cd79b, H2-ab1, H2-aa) in the PFC of LPS-treated mice. Furthermore, pretreatment with NFAT inhibitors (i.e., NFAT inhibitor and cyclosporin A) showed prophylactic effects in the LPS-treated mice. Similar to (R)-ketamine, gene knockdown of Nfatc4 gene by bilateral injection of adeno-associated virus (AAV) into the mPFC could elicit prophylactic effects in the LPS-treated mice. In conclusion, our data implicate a novel NFATc4 signaling pathway in the PFC underlying the prophylactic effects of (R)-ketamine for inflammation-related depression.
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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：
10.6
作者：
Brachman RA;McGowan JC;Perusini JN;Lim SC;Pham TH;Faye C;Gardier AM;Mendez-David I;David DJ;Hen R;Denny CA
通讯作者：
Denny CA
影响因子：
7.6
作者：
McGowan, Josephine C.;LaGamma, Christina T.;Denny, Christine A.
通讯作者：
Denny, Christine A.
DOI：
10.1007/s00406-020-01110-5
发表时间：
2020-02-20
影响因子：
4.7
作者：
Leal, Gustavo C.;Bandeira, Igor D.;Quarantini, Lucas C.
通讯作者：
Quarantini, Lucas C.
影响因子：
10.6
作者：
Berman, RM;Cappiello, A;Krystal, JH
通讯作者：
Krystal, JH