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Anti-angiogenic mechanisms and serotonergic dysfunction in the Rgs2 knockout model for the study of psycho-obstetric risk

Neuropsychopharmacology volume 49, pages 864–875 (2024)Cite this article

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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.

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Fig. 1: Behavioral testing revealed Rgs2 KO sex-specific alterations.
Fig. 2: Cortical vascular density and length is decreased in Rgs2 KO animals, though brain morphology is otherwise intact.
Fig. 3: qPCR studies of brain (cortex, paraventricular nucleus, midbrain/dorsal raphe, hindbrain) reveal changes in redox-, angiogenesis-, and GPCR-related genes in the Rgs2 KO mouse relative to wildtype (WT) comparators.
Fig. 4: Vascular density and locomotor behavior are respectively related to expression of serotonin and angiogenesis-related genes in the brain in a sex- and genotype-specific manner.
Fig. 5: Sertraline augments serotonin synaptic transmission to a greater extent in female Rgs2 KO serotonin neurons.

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Funding

Funding

This work was supported by the NIH (5T32HL007121-45 to SBG; HD089940, HD000849, RR024980, 3UL1TR002537, P50HD10355601A1 to MKS; T32 HL007344 to BMS), the American Heart Association (AHA) (18SCG34350001 and 19IPLOI34760288 to MKS; 22POST30908921 to SBG), a startup award from the University of Iowa Carver College of Medicine (SCG), and the Carver College of Medicine and Iowa Neuroscience Institute Carver Trust Early-Stage Investigator award (to SCG).

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Carver College of Medicine, University of Iowa, Iowa City, USA

    Serena B. Gumusoglu, Michaela D. Kiel, Brandon M. Schickling, Kaylee R. Weaver, Hannah R. Sullivan, Kaylie J. Coulter, Brianna M. Blaine, Mushroor Kamal, Yuping Zhang, Eric J. Devor, Donna A. Santillan & Mark K. Santillan

  2. Iowa Neuroscience Institute, University of Iowa, Iowa City, USA

    Serena B. Gumusoglu, Aleigha Gugel, Marisol C. Lauffer & Stephanie C. Gantz

  3. Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, USA

    Aleigha Gugel & Stephanie C. Gantz

  4. Neural Circuits and Behavior Core, Iowa Neuroscience Institute, University of Iowa, Iowa City, USA

    Marisol C. Lauffer

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  1. Serena B. Gumusoglu
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Contributions

SBG: Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; Drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. MKS: Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work. AG: Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work. BS: Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; Drafting the work or revising it critically for important intellectual content; final approval of the version to be published; KW: Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work. ML: Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; Drafting the work or revising it critically for important intellectual content. Hannah Sullivan: Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work. KC: Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work. BB: Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work. MKS: Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work. YZ: Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work. ED: Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; and final approval of the version to be published. DAS: Drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. SCG: Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; Drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. MKS: Drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to Mark K. Santillan.

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Competing interests

MKS is a member of the Medical Advisory Board for Comanche Pharmaceuticals and EndPreeclampsia, LLC. DAS is a member of the Medical Advisory Board for EndPreeclampsia, LLC. DAS and MKS hold patents related to the prediction and treatment of preeclampsia: US 293 #9,937,182 (April 10, 2018), EU #2,954,324, and PCT/US2018/027152. All other authors report no competing interests.

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Gumusoglu, S.B., Kiel, M.D., Gugel, A. et al. Anti-angiogenic mechanisms and serotonergic dysfunction in the Rgs2 knockout model for the study of psycho-obstetric risk. Neuropsychopharmacol. 49, 864–875 (2024). https://doi.org/10.1038/s41386-023-01749-3

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