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miR-323a regulates ERBB4 and is involved in depression

Abstract

Major depressive disorder (MDD) is a complex and debilitating illness whose etiology remains unclear. Small RNA molecules, such as micro RNAs (miRNAs) have been implicated in MDD, where they display differential expression in the brain and the periphery. In this study, we quantified miRNA expression by small RNA sequencing in the anterior cingulate cortex and habenula of individuals with MDD and psychiatrically-healthy controls. Thirty-two miRNAs showed significantly correlated expression between the two regions (False Discovery Rate < 0.05), of which four, miR-204-5p, miR-320b, miR-323a-3p, and miR-331-3p, displayed upregulated expression in MDD. We assessed the expression of predicted target genes of differentially expressed miRNAs in the brain, and found that the expression of erb-b2 receptor tyrosine kinase 4 (ERBB4), a gene encoding a neuregulin receptor, was downregulated in both regions, and was influenced by miR-323a-3p in vitro. Finally, we assessed the effects of manipulating miRNA expression in the mouse ACC on anxiety- and depressive-like behaviors. Mice in which miR-323-3p was overexpressed or knocked-down displayed increased and decreased emotionality, respectively. Additionally, these mice displayed significantly downregulated and upregulated expression of Erbb4, respectively. Overall, our findings indicate the importance of brain miRNAs in the pathology of MDD, and emphasize the involvement of miR-323a-3p and ERBB4 in this phenotype. Future studies further characterizing miR-323a-3p and neuregulin signaling in depression are warranted.

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Fig. 1: miRNAs displaying differential expression in both brain regions.
Fig. 2: Overlapping gene targets of miR-204-5p, miR-320b, miR-323a-3p, and miR-331-3p.
Fig. 3: Effects of miRNA treatment on ERBB4 expression in HEK293 cells.
Fig. 4: Manipulation of miR-323-3p in the mouse ACC modulates anxiety- and depression-like behaviors.
Fig. 5: Comparison of Human and Mouse miR-323 binding sites in the 3′UTR of ERBB4.

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Acknowledgements

GT holds a Canada Research Chair (Tier 1) and is supported by grants from the Canadian Institute of Health Research (CIHR) (FDN148374, FRN 141899, ENP161427), and by the Fonds de recherche du Québec—Santé (FRQS) (EGM141899) through the Quebec Network on Suicide, Mood Disorders and Related Disorders. This project was jointly funded by FRQS (EGM141899), the Canadian Institutes of Health Research (FRN 141899), the German Bundesministerium für Bildung and Forschung (01KU1504) and the French Agence Nationale de la Recherche (ANR-15-EPIG-0003-03 and ANR-15-EPIG-0003-04). In addition, this research was undertaken thanks in part to funding from the Canada First Research Excellence Fund, awarded to McGill University for the Healthy Brains for Healthy Lives (HBHL) initiative (4b-CF-5). AC is the incumbent of the Vera and John Schwartz Family Professorial Chair at the Weizmann Institute and is the Head of the Max Planck Society–Weizmann Institute of Science Laboratory for Experimental Neuropsychiatry and Behavioral Neurogenetics. This project was funded by the Federal Ministry of Education and Research under the funding code 01KU1501A (AC) and supported by a research grant from the Israel Science Foundation (1565/15, AC). We thank A. Varga and all the caretakers of the Max Planck Institute of Psychiatry for their devoted assistance with animal care.

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Fiori, L.M., Kos, A., Lin, R. et al. miR-323a regulates ERBB4 and is involved in depression. Mol Psychiatry (2020). https://doi.org/10.1038/s41380-020-00953-7

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