Mineralocorticoid Receptor in Glutamatergic Neurons Modulates Anxiety Exclusively in Male Mice Via Regulation of the Actin-Bundling Factor Fam107a.

Background: Exposure to stressful life events is a major risk factor for many psychiatric disorders. The mineralocorticoid receptor (MR) is a key regulator of the hypothalamic-pituitary-adrenal axis, a central stress response component. Stress-related mental disorders, such as anxiety and depression, are associated with MR dysfunction in the brain, but its cell type-specific contributions to emotional behavior and cognitive function remain unclear. Methods: Using a mouse model with a specific deletion of MR in forebrain glutamatergic neurons, we tested the behavioral, structural, and functional impact of MR in this neuronal population ( Results: We revealed a specific function of MR in regulating baseline anxiety in male but not female mice. This distinct behavioral phenotype was associated with hippocampal structural and functional alterations. Furthermore, we identified a previously unrecognized downstream target of MR, the actin-bundling factor Fam107a, whose expression is tightly regulated by MR. Overexpression of Fam107a in the hippocampus was sufficient to rescue the increased anxiety phenotype of glutamatergic MR knockout mice. Conclusions: Together, our results underline the central role of MR as a potential target in understanding the intricate interplay between stress, resilience, and mental health.