Altered offspring neurodevelopment in an arginine vasopressin preeclampsia model

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.

Abnormal cerebral microvascular perfusion and reactivity in female offspring of reduced uterine perfusion pressure (RUPP) mice model

“…The neurobiology of cognitive alterations in offspring of mothers with PE 7,53,54 is poorly understood. 55 Compatible with described alterations in brain perfusion, we also found a differential expression of angiogenic proteins that participate in signaling pathways such as inflammation, cancer, cellular stress, senescence, and apoptotic in the pup's brain of RUPP mice. In PE, cellular senescence, apoptosis resistance, and pro-inflammatory phenotype have been related mechanistically to mesenchymal stem cell dysfunction.…”

Influence of Prenatal Drug Exposure, Maternal Inflammation, and Parental Aging on the Development of Autism Spectrum Disorder

“…Infusions of AVP during pregnancy increased IL-17 levels in maternal plasma and the placenta (248), suggesting that IL-17 may also affect fetal brain development following AVP loading. To date, however, only one study has reported neurological and behavioral consequence of AVP-infused HDP in offspring (249).…”

“…Infusions of AVP during pregnancy increased IL-17 levels in maternal plasma and the placenta ( 248 ), suggesting that IL-17 may also affect fetal brain development following AVP loading. To date, however, only one study has reported neurological and behavioral consequence of AVP-infused HDP in offspring ( 249 ). Both male and female offspring that were exposed to AVP on P7 had a smaller neocortex, but caudate-putamen volume decreased in males only and increased relative to the neocortex in females.…”

“…At the behavioral level, male offspring that were exposed to AVP exhibited an increase in anxiety-like behavior in the elevated plus maze test, but females did not. Social behavior was analyzed in males only, in which an increase in sociability was observed in AVP-exposed males compared with controls ( 249 ). Further research on ASD-like phenotypes in the AVP infusion model of HDP is necessary to determine whether AVP-induced HDP recapitulates the higher risk of ASD in humans.…”

Elevated IL-6 in Pre-Eclampsia Increases Neurite Growth and Mitochondrial Respiration in an in vitro Model of Neuronal Development

“…There has been much recent interest in using rodent models to examine the brain and behaviour of offspring prenatally exposed to PE. These have yielded valuable insights into the effects of a PE-like insult on mammalian neurodevelopment, which include alterations in neuro-and gliogenesis, regional brain volumes, forebrain transcriptional pro le, and pronounced behavioural de cits [15][16][17][18]. However, there is a need to understand whether exposure to PE affects neuronal development at a single cell level, particularly in human cells.…”