Identifying Established Human Placental Markers of Schizophrenia in Rodents after Gestational Delta-9-Tetrahydrocannabinol Exposure

Placental complications resulting in fetal growth restriction (FGR) have been associated with dysregulated placental gene expression tied to an increased risk of schizophrenia (SCZ). In rat offspring, it has been demonstrated that THC exposure in pregnancy results in FGR and SCZ-like phenotypes (e.g. decreased pre-pulse inhibition of the acoustic startle response). However, it remains elusive if prenatal THC exposure induces this SCZ signature of placental gene expression. Therefore, our objective was to determine if these established predictive markers of SCZ are altered in a preclinical model of gestational oral THC exposure in rodents. We observed significantly reduced fetal weights in male and female prenatal THC-exposed offspring in the absence of maternal alterations. Placentae from THC-exposed males and females revealed altered expression of genes previously identified in human transcriptomic datasets of SCZ (i.e. Furin, Rccd1, Atp5mk), with some expression changes being sex-specific (i.e. Eif5, Rps10, Vps33b, Iqgap1). A subset of these genes was found altered in human BeWo cells exposed to THC. Targets were examined in the adult rodent (PND70) brain, and a subgroup of these genes (i.e. Furin, Rccd1) were altered concomitant with SCZ-like behaviour (decreased PPI). We further detected THC-induced upregulation of FURIN in patient-derived cerebral organoids, an effect observed in control and SCZ cell lines. Collectively, these findings demonstrate prenatal THC exposure can lead to altered gene expression in established prioritized markers of SCZ in the placenta in both animal and human models.