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

• Published in: iScience Vol. 25; no. 12; p. 105595
• Main Authors: Chen, Rosa J., Nabila, Anika, Phalke, Swati, Castro, Danny Flores, Toth, Judit Gal, Bergin, Paul, Bastiaans, Jeroen, Stuhlmann, Heidi, Pernis, Alessandra B., Toth, Miklos
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 22.12.2022; Elsevier
• Subjects: Immunology; Neuroscience; Transcriptomics; Transcriptomics; Neuroscience; Immunology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2022.105595

Serotonin-1A receptor (5HT1AR) is highly expressed in corticolimbic regions and its deficit is 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 male offspring of Het mothers, indicating sex-specific immune system abnormalities that are dependent on the mother’s 5HT1AR deficit, known as maternal genetic effect or “genetic nurture”. Expression profiling of the maternal-fetal interface revealed reduced immune cell invasion to decidua and accelerated trophoblast migration. These data suggest that 5HT1AR deficit, by altering the maternal immune system and midgestational in utero environment, leads to sex-biased outcomes, predominantly immune dysregulation in the female and anxiety-like behavior in the male offspring. [Display omitted] •5HT1AR is a risk factor in anxiety and depression•5HT1AR is linked to immune system abnormalities in females•The 5HT1AR-immunity link is indirect and due to the dam’s receptor deficit•The immune phenotype is associated with abnormal placental development Immunology; Neuroscience; Transcriptomics