[No authors listed]
The association between dysregulated serotonergic activity and major depressive disorder (MDD) is well known. However, the various mechanisms underlying serotonergic dysregulation in MDD remain unclear. Previous research on serotonergic (5-HT) neurons identified microRNA-26a (miR-26a) targeting of the serotonin autoreceptor, 5-HT receptor 1A (HTR1A). Reporter assays with the Htr1a 5'UTR sequence were performed in vitro. Adult transgenic mouse models altering miR-26a-2 and Htr1a expression were used for chronic social defeat, antidepressant treatment, and in vivo lentiviral experiments. Mice were tested for anxiety-like behavior using the elevated plus-maze, dark-light transfer, and open-field tests, and for depression-like behavior using the forced-swim test. We confirmed that miR-26a-2 downregulates Htr1a expression in 5-HT neurons in vitro. miR-26a-2 levels were significantly upregulated in the mouse dorsal raphe nucleus (DRN) following antidepressant therapy. The transgenic murine model overexpressing miR-26a-2 in serotonergic neurons displayed improved behavioral resiliency to social defeat. These effects were abrogated by the addition of Htr1a overexpression. In contrast, the transgenic murine model with miR-26a-2 knockdown in serotonergic neurons displayed increased anxious behavior and weakened antidepressant response. These effects were rescued by silencing Htr1a expression. Our findings suggest that miR-26a-2 functions as an endogenous antidepressant by targeting HTR1A in serotonergic neurons.
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