MicroRNA-26a-2 maintains stress resiliency and antidepressant efficacy by targeting the serotonergic autoreceptor HTR1A

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.