Abstract
Patients with autism spectrum disorder (ASD) typically experience substantial social isolation, which may cause secondary adverse effects on their brain development. miR-124 is the most abundant miRNA in the human brain, acting as a pivotal molecule regulating neuronal fate determination. Alterations of miR-124 maturation or expression are observed in various neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. In the present study, we analyzed a panel of brain-enriched microRNAs in serums from 2 to 6 year old boys diagnosed with ASD. The hsa-miR-124 level was found significantly elevated in ASD boys than in age and sex-matched healthy controls. In an isolation-reared weanling mouse model, we evidenced elevated mmu-miR-124 level in the serum and the medial prefrontal cortex (mPFC). These mice displayed significant sociability deficits, as well as myelin abnormality in the mPFC, which was partially rescued by expressing the miR-124 sponge in the bilateral mPFC, ubiquitously or specifically in oligodendroglia. In cultured mouse oligodendrocyte precursor cells, introducing a synthetic mmu-miR-124 inhibited the differentiation process through suppressing expression of nuclear receptor subfamily 4 group A member 1 (Nr4a1). Overexpressing Nr4a1 in the bilateral mPFC also corrected the social behavioral deficits and myelin impairments in the isolation-reared mice. This study revealed an unanticipated role of the miR-124/Nr4a1 signaling in regulating early social experience-dependent mPFC myelination, which may serve as a potential therapy target for social neglect or social isolation-related neuropsychiatric disorders.
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Acknowledgements
We thank Mr. Zhengrong Xia for technical assistance with the EM and Dr. Yongjie Zhang for technical assistance with the OLs culture.
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This work was supported by the grants from by the National Natural Science Foundation of China (81801378 and 81871117).
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MX, CS and HH designed the experiments. YZ and YP performed most of the experiments and analysis, YZ, YP, WF, YJ, SC, SD, ZW, ZY, LY, TW, PS, GJ, ZY and YZ did the behavioral experiment. The manuscript was written by MX, CS, YZ and CM. All authors discussed results, made Figures, and edited the manuscript.
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Zhang, Y., Pang, Y., Feng, W. et al. miR-124 regulates early isolation-induced social abnormalities via inhibiting myelinogenesis in the medial prefrontal cortex. Cell. Mol. Life Sci. 79, 507 (2022). https://doi.org/10.1007/s00018-022-04533-6
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DOI: https://doi.org/10.1007/s00018-022-04533-6