Altered offspring neurodevelopment in an arginine vasopressin preeclampsia model

Serena Banu Gumusoglu,Sabrina Marie Scroggins,Akanksha Sri Satya Chilukuri,Benjamin Wen Qing Hing,Mark Kharim Santillan,Donna Ann Santillan,Hanna Elizabeth Stevens,Justin Lewis Grobe,Sreelekha Kundu,Jeremy Anton Sandgren

doi:10.1038/s41398-021-01205-0

Serena Banu Gumusoglu, Sabrina Marie Scroggins + Show 8 more

Open Access

https://doi.org/10.1038/s41398-021-01205-0

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Abstract

Preeclampsia is a severe gestational hypertensive condition linked to child neuropsychiatric disorders, although underlying mechanisms are unclear. We used a recently developed, clinically relevant animal model of preeclampsia to assess offspring. C57BL/6J mouse dams were chronically infused with arginine vasopressin (AVP) or saline (24 ng/h) throughout pregnancy. Adult offspring were behaviorally tested (Y-maze, open field, rotarod, social approach, and elevated plus maze). Offspring brain was assessed histologically and by RNA sequencing. Preeclampsia-exposed adult males exhibited increased anxiety-like behavior and social approach while adult females exhibited impaired procedural learning. Adult AVP-exposed males had reduced total neocortical volume. Adult AVP-exposed females had increased caudate–putamen volume, increased caudate–putamen cell number, and decreased excitatory synapse density in hippocampal dentate gyrus (DG), CA1, and CA3. At postnatal day 7 (P7), AVP-exposed male and female offspring both had smaller neocortex. At P7, AVP-exposed males also had smaller caudate–putamen volume, while females had increased caudate–putamen volume relative to neocortical size. Similar to P7, E18 AVP-exposed offspring had smaller dorsal forebrain, mainly in reduced intermediate, subventricular, and ventricular zone volume, particularly in males. Decreased volume was not accounted for by cell size or cerebrovascular vessel diameter changes. E18 cortical RNAseq revealed 49 differentially-expressed genes in male AVP-exposed offspring, over-representing cytoplasmic translation processes. In females, 31 genes were differentially-expressed, over-representing collagen-related and epithelial regulation pathways. Gene expression changes in E18 AVP-exposed placenta indicated potential underlying mechanisms. Deficits in behavior and forebrain development in this AVP-based preeclampsia model were distinctly different in males and females, implicating different neurobiological bases.

Highlights

Preeclampsia is a gestational hypertensive condition with no corrective treatment aside from delivery
Gestational and offspring growth outcomes As previously reported[15], arginine vasopressin (AVP)-infused dams had higher urine protein at E18 [mean ± SEM; saline: 1.10 ± 0.23 ng/ μL, AVP: 3.00 ± 0.50 ng/μL; t(9)=3.66, p = 0.005)], indicating the renal dysfunction that is cardinal to preeclampsia[31]
Offspring body size at E14 was unaffected by maternal AVP infusion (Supplementary Fig. 1A), but AVP-exposed offspring weighed less at E18 [main effect of AVP by two-way ANOVA p < 0.001, F1,58 = 15.10); AVP-exposed E18 males weighed significantly less and females trended smaller [posthoc t-test males: t(36) = 3.375, p = 0.0018; females: t(22) = 2.275, p = 0.033, corrected alpha = 0.025] (Supplementary Fig. 1B)

Summary

Introduction

Preeclampsia is a gestational hypertensive condition with no corrective treatment aside from delivery. Preeclampsia exposure is linked to neuropsychiatric outcomes in exposed children[3], including increased rates of autism spectrum disorder (ASD), attention deficit hyperactivity disorder, and cognitive deficits[4,5,6,7,8,9,10]. Preeclampsia-exposed children exhibit altered brain tractography, resting-state functional connectivity, and cerebrovasculature[11,12,13]. Despite an epidemiological connection between preeclampsia and altered offspring neurodevelopment, the underlying mechanism by which offspring neurobiology and behavior is altered is poorly understood. Multiple animal models have been developed to uncover preeclampsia mechanisms. One unique mouse model of preeclampsia involves continuous maternal administration of arginine vasopressin (AVP) throughout pregnancy[14,15].

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