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.
Highlights
Neuroinflammatory changes, including glial activation and subsequent production of inflammatory cytokines, are observed in neurodegenerative diseases and normal aging[1]
Dicer knockout in astrocytes Glial fibrillary acidic protein (GFAP) is the commonly used marker for astrocyte, and its expression increased in the activated astroglia[13]
Dicer KO-Astrocyte-conditioned medium (ACM) We explored the effect of CCL5 on synaptic formation
Summary
Neuroinflammatory changes, including glial activation and subsequent production of inflammatory cytokines, are observed in neurodegenerative diseases and normal aging[1]. Official journal of the Cell Death Differentiation Association. Sun et al Cell Death and Disease (2019)10:141. MiRNAs with important functions in synaptic and other homeostatic processes are differentially regulated in the ageing human brain[10]. Neuronal Dicer ablation demonstrated that a functional neuronal miRNA system is absolutely crucial for both the correct development of the nervous system as a whole and for the differentiation, proper function, and survival of individual neurons[11]. Increasing studies have implicated astrocytes have a pivotal role in synapse formation and function, still little is known about the astroglial miRNAs in the regulation of synaptic development, and the potential effects of astroglial miRNAs dysfunction in the pathophysiology of aging, neurodevelopmental disorders, and neurodegenerative disorders
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