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.

精神疾病和产科疾病对公共健康的威胁越来越大，并且共病率很高。 G蛋白偶联受体信号传导（例如，加压素、血清素）可能是一种聚合心理产科风险机制。 G 蛋白信号转导调节因子 2 ( RGS2)突变会增加妊娠期疾病先兆子痫和抑郁症的风险。我们之前在小鼠中发现了类似先兆子痫的抗血管生成产科表型，其胎盘Rgs2表达降低。在这里，我们将其扩展到测试Rgs2 KO 小鼠中保守的脑血管和血清素能机制是否也与神经生物学表型的风险相关。 Rgs2 KO 表现出焦虑、抑郁和享乐样行为。 Rgs2 KO 中皮质血管密度和血管长度减少；皮质和白质厚度以及细胞密度没有变化。在Rgs2 KO 中，血清素能基因表达发生了性别特异性变化（例如，女性中皮质Htr2a、Maoa增加，但男性中所有血清素目标未改变或减少）；室旁核和主动脉氧化还原相关表达增加；男性皮层中的血管生成基因表达发生了变化，但女性皮层中没有变化。中缝背侧血清素神经元的全细胞记录显示，雌性而非雄性 KO 神经元中的 5-HT1A 受体依赖性抑制性突触后电流 (5-HT1A-IPSC) 发生了改变。此外，SSRI 舍曲林对 5-羟色胺转运蛋白的阻断使 KO 神经元中 5-HT1A-IPSC 的振幅和达到峰值的时间比仅在雌性中的 WT 神经元中更大程度地增加。 这些结果证明了Rgs2 KO 中的行为、脑血管和舍曲林过敏表型，其中一些是性别特异性的。血管和细胞应激机制可能会导致破坏，这些机制将精神疾病和产科疾病的共同发病机制联系起来，以揭示未来的目标。