Astrocytic miR-324-5p is essential for synaptic formation by suppressing the secretion of CCL5 from astrocytes

Abstract

There is accumulating evidence that astrocytes play an important role in synaptic formation, plasticity, and pruning. Dicer and the fine-tuning of microRNA (miRNA) network are important for maintaining the normal functions of central nervous system and dysregulation of miRNAs is implicated in neurological disorders. However, little is known about the role of Dicer and miRNAs of astrocytes in the homeostasis of synapse as well as its plasticity. By selectively deleting Dicer in postnatal astrocytes, Dicer-deficient mice exhibited reactive astrogliosis and deficits in dendritic spine formation. Astrocyte-conditioned medium (ACM) collected from Dicer-null astrocytes caused synapse degeneration in cultured primary neurons. The expression of chemokine ligand 5 (CCL5) elevated in Dicer-deleted astrocytes which led to the significant augmentation of secreted CCL5 in ACM. In neurons treated with Dicer KO-ACM, CCL5 supplementation inhibited MAPK/CREB signaling pathway and exacerbated the synaptic formation deficiency, while CCL5 knockdown partially rescued the synapse degeneration. Moreover, we validated CCL5 as miR-324-5p targeted gene. ACM collected from miR-324-5p antagomir-transfected astrocytes mimicked the effect of CCL5 treatment on inhibiting synapse formation and MAPK/CREB signaling in Dicer KO-ACM-cocultured neurons. Furthermore, decreased miR-324-5p expression and elevated CCL5 expression were observed in the brain of aging mice. Our work reveals the non-cell-autonomous roles of astroglial miRNAs in regulation of astrocytic secretory milieu and neuronal synaptogenesis, implicating the loss or misregulation of astroglial miRNA network may contribute to neuroinflammation, neurodegeneration, and aging.

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Item Type:	Article
Authors/Creators:	Sun, C. Zhu, L. Ma, R. Ren, J. Wang, J. Gao, S. Yang, D. Ning, K. https://orcid.org/0000-0002-0771-1134 Ling, B. Lu, B. Chen, X. Xu, J.
Copyright, Publisher and Additional Information:	© The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Dates:	Accepted: 4 January 2019 Published (online): 13 February 2019 Published: 13 February 2019
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Sheffield Teaching Hospitals
Funding Information:	Funder Grant number MEDICAL RESEARCH COUNCIL MR/M010864/1 MEDICAL RESEARCH COUNCIL MR/K008943/1
Depositing User:	Symplectic Sheffield
Date Deposited:	28 Feb 2019 12:58
Last Modified:	28 Feb 2019 12:58
Published Version:	https://doi.org/10.1038/s41419-019-1329-3
Status:	Published
Publisher:	Springer Nature
Refereed:	Yes
Identification Number:	10.1038/s41419-019-1329-3
Related URLs:	PubMed URL
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:142617

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Astrocytic miR-324-5p is essential for synaptic formation by suppressing the secretion of CCL5 from astrocytes

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