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.

精神科和产科疾病对公共卫生的威胁越来越大，合并症的发生率也很高。G 蛋白偶联受体信号转导（例如加压素、5-羟色胺）可能是一种趋同的产科心理风险机制。G 蛋白信号转导 2 （RGS2） 突变调节因子会增加妊娠期子痫前期和抑郁症的风险。我们之前在小鼠中发现了子痫前期样、抗血管生成产科表型，胎盘 Rgs2 表达降低。在这里，我们将其扩展到测试保守的脑血管和血清素能机制是否也与 Rgs2 KO 小鼠的神经生物学表型风险相关。Rgs2KO 表现出焦虑、抑郁和享乐样行为。Rgs2 KO 中的皮质血管密度和血管长度降低;皮质和白质厚度以及细胞密度保持不变。在 Rgs2 KO 中，5-羟色胺能基因表达发生性别特异性改变（例如，女性皮质 Htr2a、Maoa 增加，但男性所有 5-羟色胺靶标保持不变或降低）;氧化还原相关表达在室旁核和主动脉中增加;血管生成基因表达在雄性皮层中发生变化，而在雌性皮层中未发生改变。来自中缝背侧 5-羟色胺神经元的全细胞记录显示，女性而非雄性 KO 神经元中 5-HT1A 受体依赖性抑制性突触后电流 （5-HT1A-IPSC） 发生改变。此外，SSRI 舍曲林阻断 5-羟色胺转运蛋白比仅在女性的 WT 神经元中增加 5-HT1A-IPSCs 的振幅和达到峰值的时间更大。 这些结果表明 Rgs2 KOs 中的行为、脑血管和舍曲林超敏反应表型，其中一些是性别特异性的。干扰可能是由血管和细胞应激机制驱动的，这些机制将精神科和产科疾病的共同发病机制联系起来，以揭示未来的靶点。