星形胶质细胞5-HT1A受体介导雄性小鼠年龄依赖性海马LTD和恐惧记忆消退-动脉网

Astrocytic 5-HT1A receptor mediates age-dependent hippocampal LTD and fear memory extinction in male mice

Nature 等信源发布 2024-08-01 07:21

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AbstractNMDA receptor-dependent long-term depression (LTD) in the hippocampus is a well-known form of synaptic plasticity that has been linked to different cognitive functions. Although the underlying mechanisms remain unclear, this form of LTD cannot be induced by low-frequency stimulation (LFS) in adult mice.

海马NMDA受体依赖性长期抑郁（LTD）是一种众所周知的突触可塑性形式，与不同的认知功能有关。尽管潜在的机制尚不清楚，但这种形式的LTD不能通过成年小鼠的低频刺激（LFS）诱导。

In this study, we found that LFS-induced LTD was not easily induced in adult animals and was age dependent. Interestingly, the level of the 5-HT1A receptor was correspondingly increased and exhibited an inverse correlation with the magnitude of LFS-LTD during development. Knockout or pharmacological inhibition of the 5-HT1A receptor reversed impaired LFS-LTD in adult mice (P60), while activation or inhibition of this receptor disturbed or enhanced LFS-LTD in adolescent mice (P21), respectively.

在这项研究中，我们发现LFS诱导的LTD在成年动物中不容易诱导，并且与年龄有关。有趣的是，5-HT1A受体的水平相应增加，并且在发育过程中与LFS-LTD的大小呈负相关。5-HT1A受体的敲除或药理学抑制逆转了成年小鼠（P60）中受损的LFS-LTD，而该受体的激活或抑制分别干扰或增强了青春期小鼠（P21）中的LFS-LTD。

Furthermore, the astrocytic 5-HT1A receptor in the hippocampus predominantly mediated age-dependent LFS-LTD through enhancing GABAergic neurotransmission. Finally, fear memory extinction differed among the above conditions. These observations enrich our knowledge of LTD at the cellular level and suggest a therapeutic approach for LTD-related psychiatric disorders..

此外，海马中的星形胶质细胞5-HT1A受体主要通过增强GABA能神经传递来介导年龄依赖性LFS-LTD。最后，恐惧记忆消退在上述条件下有所不同。这些观察结果丰富了我们在细胞水平上对LTD的了解，并为LTD相关的精神疾病提供了治疗方法。。

IntroductionLong-term depression (LTD) in the CNS has been the subject of intense investigation as a mechanism that may be involved in learning and memory and in various pathological conditions1,2,3. NMDA receptor-dependent LTD in the hippocampus is a well-known form of synaptic plasticity that has been linked to different cognitive functions4,5.

引言中枢神经系统中的长期抑郁症（LTD）作为一种可能参与学习和记忆以及各种病理状况的机制，一直是深入研究的主题1,2,3。海马中NMDA受体依赖性LTD是一种众所周知的突触可塑性形式，与不同的认知功能有关4,5。

Hippocampal LTD can be experimentally induced by several different types of electrical and pharmacological stimulation methods. The most commonly used method for inducing LTD involves prolonged low-frequency stimulation (LFS) at 0.5–5 Hz6,7,8,9. Despite considerable progress in understanding the cellular and molecular mechanisms underlying LTD, LTD is difficult to elicit and less robust in hippocampal slices from adult animals than in slices from young animals10,11,12,13,14,15,16,17.

海马LTD可以通过几种不同类型的电刺激和药物刺激方法进行实验诱导。诱导LTD最常用的方法是在0.5-5hz6,7,8,9延长低频刺激（LFS）。尽管在理解LTD的细胞和分子机制方面取得了相当大的进展，但LTD在成年动物的海马切片中难以引发，并且比年轻动物的切片更不稳定10,11,12,13,14,15,16,17。

However, the mechanisms underlying the age-related decrease in the magnitude of LTD remain elusive.The serotonergic (5-HT) system is implicated in the neurobiological control of learning and memory and synaptic plasticity18,19. This system matures during early postnatal development, during which time it plays an important role in establishing circuits that mediate synaptic plasticity20.

然而，与年龄相关的LTD幅度下降的潜在机制仍然难以捉摸。5-羟色胺能（5-HT）系统与学习记忆和突触可塑性的神经生物学控制有关18,19。该系统在出生后早期发育过程中成熟，在此期间，它在建立介导突触可塑性的回路中起着重要作用20。

Once the 5-HT system has matured, it is well positioned for shape development20. Within the 5-HT system, signaling through the inhibitory serotonergic 1 A (5-HT1A) receptor is required for the normal development of circuits that subserve brain functions in mice20,21,22,23. The 5-HT1A receptor is an inhibitory G protein-coupled receptor expressed both in serotonergic neurons and in target areas receiving serotonergic innervation24,25 and has been reported to play a crucial role in brain dysfunction, including alcoholism, cocaine abuse, Alzheimer’s disease, and schizo.

一旦5-HT系统成熟，它就可以很好地进行形状开发20。在5-HT系统中，通过抑制性5-羟色胺能1A（5-HT1A）受体发出信号是正常发育维持小鼠大脑功能的电路所必需的20,21,22,23。5-HT1A受体是一种抑制性G蛋白偶联受体，在5-羟色胺能神经元和接受5-羟色胺能神经支配的靶区域表达[24,25]，据报道在脑功能障碍中起关键作用，包括酒精中毒，可卡因滥用，阿尔茨海默病和精神分裂症。

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Download referencesAcknowledgementsWe thank T.M. Gao (Southern Medical University, Guangzhou, China) for providing the aldh1l1-CreERT2 mice. This work was supported by the National Natural Science Foundation of China (82071488, 82271525) and the Natural Science Foundation of Guangdong Province (2023A1515010456, 2024A1515030100).Author informationAuthor notesThese authors contributed equally: Qian-Yun Wu, Lian-Hong Lin, Kun Lu.Authors and AffiliationsDepartment of Psychiatry, Institute of Brain Disease, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, ChinaQian-Yun Wu, Lian-Hong Lin, Si-Fu Deng, Wei-Min Li, Yuan Xu, Bin Zhang & Ji-Hong LiuGuangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou, 510515, ChinaQian-Yun Wu, Lian-Hong Lin, Si-Fu Deng, Wei-Min Li, Yuan Xu, Bin Zhang & Ji-Hong LiuDepartment of Pediatric Orthopaedic, Zhengzhou Orthopaedics Hospital, Zhengzhou, 450052, ChinaKun LuAuthorsQian-Yun WuView author publicationsYou can also search for this author in.

下载参考文献致谢我们感谢T.M.Gao（中国广州南方医科大学）提供aldh1l1-CreERT2小鼠。这项工作得到了国家自然科学基金（8207148882271525）和广东省自然科学基金（2023A15150104562024A1515030100）的支持。作者信息作者注意到这些作者做出了同样的贡献：吴倩芸，林连红，卢坤。作者和附属机构南方医科大学南方医院脑疾病研究所精神病学系，广州，510515，中国吴倩芸，林连红，邓四福，李伟民，袁旭，张斌和刘继红广东港澳大湾区脑科学和脑启发智力中心，广州，510515，中国吴倩芸，林连红，邓四福，李伟民，袁旭，张斌和刘继红郑州骨科医院儿科骨科，郑州，450052，卢坤作者wView作者出版物您也可以在中搜索此作者。

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PubMed Google ScholarContributionsJ.H.L. designed the study. J.H.L., Q.Y.W., and K.L. performed the behavior tests and analysis. J.H.L. and W.M.L. performed the electrophysiology recordings. Q.Y.W. and K.Z. conducted the ELISA measurements. Q.Y.W. and S.F.D. performed the immunofluorescence.

PubMed谷歌学术贡献。H、 L.设计了这项研究。J、 H.L.，Q.Y.W。和K.L.进行了行为测试和分析。J、 H.L.和W.M.L.进行了电生理记录。Q、 Y.W.和K.Z.进行了ELISA测量。Q、。

L.H.L. and Y.X. conducted the stereotaxic microinjection. L.H.L. and Y.X. performed the western blotting. J.H.L. conceived the project and wrote the manuscript with the assistance of B.Z. All the authors approved the final manuscript.Corresponding authorsCorrespondence to.

五十、 H.L.和Y.X.进行了立体定向显微注射。五十、 H.L.和Y.X.进行了蛋白质印迹。J、 H.L.在B.Z.的帮助下构思了这个项目并撰写了手稿。所有作者都批准了最终手稿。通讯作者通讯。

Bin Zhang or Ji-Hong Liu.Ethics declarations

张斌或刘纪红。道德宣言

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The authors declare no competing interests.

作者声明没有利益冲突。

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Reprints and permissionsAbout this articleCite this articleWu, QY., Lin, LH., Lu, K. et al. Astrocytic 5-HT1A receptor mediates age-dependent hippocampal LTD and fear memory extinction in male mice.

转载和许可本文引用本文Wu，QY。，林，左侧。，Lu，K。等人。星形胶质细胞5-HT1A受体介导雄性小鼠的年龄依赖性海马LTD和恐惧记忆消退。

Exp Mol Med (2024). https://doi.org/10.1038/s12276-024-01285-0Download citationReceived: 02 January 2024Revised: 09 April 2024Accepted: 02 May 2024Published: 01 August 2024DOI: https://doi.org/10.1038/s12276-024-01285-0Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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