Identifying established human placental markers of schizophrenia in rodents after gestational ∆9-tetrahydrocannabinol exposure†.

Placental complications resulting in fetal growth restriction have been associated with dysregulated placental gene expression tied to an increased risk of schizophrenia. In rat offspring, it has been demonstrated that ∆9-tetrahydrocannabinol exposure in pregnancy results in fetal growth restriction and schizophrenia-like phenotypes (e.g., decreased pre-pulse inhibition of the acoustic startle response). However, it remains elusive if prenatal ∆9-tetrahydrocannabinol exposure induces this schizophrenia signature of placental gene expression. Therefore, our objective was to determine if these established predictive markers of schizophrenia are altered in a preclinical model of gestational oral ∆9-tetrahydrocannabinol exposure in rodents. We observed significantly reduced fetal weights in male and female prenatal ∆9-tetrahydrocannabinol-exposed offspring in the absence of maternal pregnancy outcomes. Placentae from ∆9-tetrahydrocannabinol-exposed males and females revealed altered expression of genes previously identified in human transcriptomic datasets of schizophrenia (i.e., Furin, Rccd1, and Atp5mk), with some expression changes being sex-specific (i.e., Eif5, Rps10, Vps33b, and Iqgap1). A subset of these genes were found differentially expressed in human BeWo cells exposed to ∆9-tetrahydrocannabinol. Targets were next examined in the adult rodent (postnatal day70) brain, and a subgroup of these genes (i.e., Furin, Rps10, and Rccd1) were increased concomitant with schizophrenia-like behavior (e.g., decreased pre-pulse inhibition). We further detected ∆9-tetrahydrocannabinol-induced upregulation of FURIN in patient-derived cerebral organoids, an effect observed in both control and schizophrenia cell lines. Collectively, these findings demonstrate prenatal ∆9-tetrahydrocannabinol exposure can lead to altered gene expression in established prioritized markers of schizophrenia in the placenta in both animal and human models.