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

TL;DR

Deleting the mineralocorticoid receptor in brain cells increases anxiety in male mice, and this effect can be reversed by boosting a protein called Fam107a.

Contribution

Identified a sex-specific role of MR in glutamatergic neurons and a novel downstream target, Fam107a, in anxiety regulation.

Findings

MR in glutamatergic neurons regulates baseline anxiety exclusively in male mice.

MR deletion leads to hippocampal structural and functional changes in male mice.

Overexpression of Fam107a rescues increased anxiety in MR-deficient male mice.

Abstract

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.

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 (n = 9–14 for behavioral and n = 3–4 for structural and functional analyses).

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.

Together, our results underline the central role of MR as a potential target in understanding the intricate interplay between stress, resilience, and mental health.

Stressful experiences are a significant risk factor for psychiatric disorders, including anxiety and depression. At the core of the body’s stress response is the hypothalamic-pituitary-adrenal (HPA) axis, which is tightly regulated by the mineralocorticoid receptor (MR). While we know that MR dysfunction is linked to stress-related mental health issues, its specific function within different types of brain cells has been largely unknown. In this study, we investigated the role of MR in glutamatergic neurons, the brain’s primary excitatory cell type. Using a mouse model with a targeted deletion of the MR gene in these specific neurons, we discovered a key function of MR in regulating baseline anxiety. Notably, this effect was observed exclusively in male mice; female mice were unaffected. This sex-specific behavioral change was associated with structural and functional alterations in the hippocampus, a brain region critical for emotion and memory. Further investigation revealed a novel downstream target of MR: the actin-bundling protein FAM107a. We found that MR tightly regulates the expression of this protein. Remarkably, when we increased the expression of FAM107a in the hippocampus of the MR-deficient male mice, it was sufficient to partially rescue their increased anxiety phenotype. Our findings demonstrate a direct link between MR in glutamatergic neurons and anxiety, highlighting a previously unappreciated sex-specific mechanism. By identifying FAM107a as a critical downstream target, we have uncovered a new potential pathway for therapeutic intervention.

Stressful experiences are a significant risk factor for psychiatric disorders, including anxiety and depression. At the core of the body’s stress response is the hypothalamic-pituitary-adrenal (HPA) axis, which is tightly regulated by the mineralocorticoid receptor (MR). While we know that MR dysfunction is linked to stress-related mental health issues, its specific function within different types of brain cells has been largely unknown. In this study, we investigated the role of MR in glutamatergic neurons, the brain’s primary excitatory cell type. Using a mouse model with a targeted deletion of the MR gene in these specific neurons, we discovered a key function of MR in regulating baseline anxiety. Notably, this effect was observed exclusively in male mice; female mice were unaffected. This sex-specific behavioral change was associated with structural and functional alterations in the hippocampus, a brain region critical for emotion and memory. Further investigation revealed a novel downstream target of MR: the actin-bundling protein FAM107a. We found that MR tightly regulates the expression of this protein. Remarkably, when we increased the expression of FAM107a in the hippocampus of the MR-deficient male mice, it was sufficient to partially rescue their increased anxiety phenotype. Our findings demonstrate a direct link between MR in glutamatergic neurons and anxiety, highlighting a previously unappreciated sex-specific mechanism. By identifying FAM107a as a critical downstream target, we have uncovered a new potential pathway for therapeutic intervention.

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