Journal article
Anti-angiogenic mechanisms and serotonergic dysfunction in the Rgs2 knockout model for the study of psycho-obstetric risk
Neuropsychopharmacology (New York, N.Y.), Vol.49(5), pp.864-875
04/2024
DOI: 10.1038/s41386-023-01749-3
PMCID: PMC10948883
PMID: 37848733
Abstract
Psychiatric and obstetric diseases are growing threats to public health and share high rates of co-morbidity. G protein-coupled receptor signaling (e.g., vasopressin, serotonin) may be a convergent psycho-obstetric risk mechanism. Regulator of G Protein Signaling 2 (RGS2) mutations increase risk for both the gestational disease preeclampsia and for depression. We previously found preeclampsia-like, anti-angiogenic obstetric phenotypes with reduced placental Rgs2 expression in mice. Here, we extend this to test whether conserved cerebrovascular and serotonergic mechanisms are also associated with risk for neurobiological phenotypes in the Rgs2 KO mouse. Rgs2 KO exhibited anxiety-, depression-, and hedonic-like behaviors. Cortical vascular density and vessel length decreased in Rgs2 KO; cortical and white matter thickness and cell densities were unchanged. In Rgs2 KO, serotonergic gene expression was sex-specifically changed (e.g., cortical Htr2a, Maoa increased in females but all serotonin targets unchanged or decreased in males); redox-related expression increased in paraventricular nucleus and aorta; and angiogenic gene expression was changed in male but not female cortex. Whole-cell recordings from dorsal raphe serotonin neurons revealed altered 5-HT1A receptor-dependent inhibitory postsynaptic currents (5-HT1A-IPSCs) in female but not male KO neurons. Additionally, serotonin transporter blockade by the SSRI sertraline increased the amplitude and time-to-peak of 5-HT1A-IPSCs in KO neurons to a greater extent than in WT neurons in females only. These results demonstrate behavioral, cerebrovascular, and sertraline hypersensitivity phenotypes in Rgs2 KOs, some of which are sex-specific. Disruptions may be driven by vascular and cell stress mechanisms linking the shared pathogenesis of psychiatric and obstetric disease to reveal future targets.
Details
- Title: Subtitle
- Anti-angiogenic mechanisms and serotonergic dysfunction in the Rgs2 knockout model for the study of psycho-obstetric risk
- Creators
- Serena B Gumusoglu - University of IowaMichaela D Kiel - University of IowaAleigha Gugel - University of IowaBrandon M Schickling - University of IowaKaylee R WeaverMarisol C Lauffer - University of IowaHannah R Sullivan - University of IowaKaylie J Coulter - University of IowaBrianna M Blaine - University of IowaMushroor KamalYuping Zhang - University of IowaEric J Devor - University of IowaDonna A Santillan - University of IowaStephanie C Gantz - University of IowaMark K Santillan - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Neuropsychopharmacology (New York, N.Y.), Vol.49(5), pp.864-875
- DOI
- 10.1038/s41386-023-01749-3
- PMID
- 37848733
- PMCID
- PMC10948883
- NLM abbreviation
- Neuropsychopharmacology
- ISSN
- 0893-133X
- eISSN
- 1740-634X
- Grant note
- DOI: 10.13039/100000002, name: U.S. Department of Health & Human Services | National Institutes of Health, award: 5T32HL007121-45, T32 HL007344, HD089940, HD000849, RR024980, 3UL1TR002537, P50HD10355601A1; DOI: 10.13039/100000968, name: American Heart Association, award: 22POST30908921, 18SCG34350001, 19IPLOI34760288; name: Iowa Medical Student Research Program Summer Fellowship; name: U.S. Department of Health & Human Services | National Institutes of Health; name: University of Iowa Summer Undergraduate Research Fellowship; name: Carver College of Medicine and Iowa Neuroscience Institute Carver Trust Early-Stage Investigator award; name: U.S. Department of Health & Human Services | National Institutes of Health; name: U.S. Department of Health & Human Services | National Institutes of Health; name: U.S. Department of Health & Human Services | National Institutes of Health; name: U.S. Department of Health & Human Services | National Institutes of Health; name: U.S. Department of Health & Human Services | National Institutes of Health
- Language
- English
- Electronic publication date
- 10/17/2023
- Date published
- 04/2024
- Academic Unit
- Molecular Physiology and Biophysics; Psychological and Brain Sciences; Iowa Neuroscience Institute; Obstetrics and Gynecology; Dental Research
- Record Identifier
- 9984482558002771
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