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Serotonin-1A receptor, a psychiatric disease risk factor, modulates offspring immunity via sex-dependent genetic nurture

ABSTRACT: Serotonin-1A receptor (5HT1AR) is highly expressed in corticolimbic regions and its deficit has been associated with anxiety and depression. A similar reduction in 5HT1AR heterozygous knockout (Het) mice results in anxiety-like and increased stress-reactivity phenotypes. Here we describe immunological abnormalities in Het females, characterized by an activated state of innate and adaptive immune cells. Het males showed only limited immune dysregulation. Similar immune abnormalities were present in the genetically WT female (F1) but not in male offspring of Het mothers, indicating sex-specific immune system abnormalities that are unrelated to the individual’s receptor expression but instead dependent on the mother’s 5HT1AR deficit, known as a maternal genetic effect or “genetic nurture”. Studying the maternal-fetal interface by scRNA-seq revealed reduced immune cell invasion to the decidua and accelerated trophoblast migration that was normalized by term. Despite these phenotypes, 5HT1AR is not, or only minimally expressed in the immune system and placenta, raising the possibility of a central regulation of the immune system by highly expressed brain receptors. We conclude that 5HT1AR deficit, by altering the maternal immune system and midgestational in utero environment, leads to sex-biased outcomes, predominantly immune dysregulation in females and anxiety-like behavior in males.

ORGANISM(S): Mus musculus

PROVIDER: GSE217086 | GEO | 2022/11/29

REPOSITORIES: GEO

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Project description:Background: Major depressive disorder (MDD) is a recurring affective disorder that is two times more prevalent in females than males. Evidence supports immune system dysfunction as a major contributing factor to MDD, notably in a sexually dimorphic manner. Nuclear factor erythroid 2-related factor 2 (Nrf2), a regulator of antioxidant signaling during inflammation, is dysregulated in many chronic inflammatory disorders, however its role in depression and the associated sex differences have yet to be explored. Here we investigated the sex-specific antidepressant and immunomodulatory effects of the potent Nrf2 activator dimethyl fumarate (DMF), as well as the associated gene expression profiles. Methods: Male and female rats were treated with vehicle or DMF (25 mg/kg) while subjected to 8 weeks of chronic unpredictable stress. The effect of DMF treatment on stress-induced depression- and anxiety-like behaviours, as well as deficits in recognition and spatial learning and memory were then assessed. Hippocampal (HIP) microglial activation and alterations in gene transcripts were also evaluated. Results: DMF treatment during stress exposure had antidepressant effects in male but not female rats, with no anxiolytic effects in either sex. Recognition learning and memory and spatial learning and memory were impaired in chronically stressed males and females, respectively, however DMF treatment rescued these deficits. DMF treatment also prevented stress-induced HIP microglial activation in males. Conversely, females displayed no HIP microglial activation associated with stress exposure. Lastly, chronic stress elicited sex-specific alterations in HIP gene expression, many of which were normalized in animals treated with DMF. Of note, several differentially expressed genes in males were related to inflammatory or immune responses. Conclusions: Collectively, these findings support a greater role of immune processes in males than females in a rodent model of depression. This suggests that pharmacotherapies that target Nrf2 have the potential to be an effective sex-specific treatment for depression. Major depressive disorder is two times more prevalent in females than males. Further, immune system dysfunction has been shown to contribute to the development of depression, with previous studies consistently reporting chronic low-grade inflammation in depressed individuals. Not surprisingly, the immune system dysfunction associated with depression appears to be sex specific. As such, while anti-inflammatory drugs have shown antidepressant effects in preclinical studies, the sex differences in these effects are seldomly investigated. Thus, this study sought to determine the sex-specific antidepressant and immune modulatory effects of dimethyl fumarate (DMF) treatment. DMF is a drug that activates the protein nuclear factor erythroid 2-related factor 2 to initiate anti-inflammatory signaling pathways. Here, male and female rats were exposed to 8 weeks of chronic stress while receiving daily DMF treatment. Subsequently, their expression of depression- and anxiety-like behaviours, as well as learning and memory deficits were assessed. Changes in the levels of an inflammatory marker in the brain and alterations in gene expression were also evaluated. DMF treatment had antidepressant effects in male rats only but did not have anti-anxiety effects in either sex. The learning and memory deficits in both sexes were rescued with DMF treatment. Notably, chronic stress only increased inflammatory marker levels in male rats, which was prevented by DMF treatment. Additionally, DMF normalized several of the sex-specific gene alterations induced by chronic stress, with many of the male-specific genes relating to inflammatory processes. These data suggest that anti-inflammatory drugs may be an effective antidepressant treatment in males.

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Serotonin-1A receptor, a psychiatric disease risk factor, modulates offspring immunity via sex-dependent genetic nurture

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