Abstract
Cortical heterotopias are clusters of ectopic neurons in the brain, and are commonly associated with pharmaceutical resistant epilepsy in patients. We have previously characterized the robust penetrance of a cortical heterotopia in a rat model, induced by thyroid hormone (TH) disruption during gestation. However, how maternal TH insufficiency results in this birth defect is unknown. Here we first determined the developmental window susceptible to endocrine disruption, and describe a cellular mechanism responsible for its formation. We show that five days of maternal goitrogen treatment (10 ppm propylthiouracil) during the perinatal period (GD19-PN2) induces a periventricular heterotopia in 100% of the offspring; this period corresponds to the second trimester in humans. Beginning in the perinatal brain, neurons begin to aggregate near the ventricles of treated animals. In parallel, cellular changes of the ventricular epithelium were observed, including abnormal cell adhesion and altered progenitor cell morphology. As the ventricular epithelium is juxtaposed to both the cerebrospinal fluid and vasculature, two sources of brain THs, this stem cell niche may be especially susceptible to TH disruption. We are now performing RNA sequencing of the ventricular epithelium in both euthyroid and hypothyroid neonates to investigate how THs are affecting this cell population. This work highlights the spatiotemporal vulnerabilities of the developing brain, and suggests that maintenance of euthyroidism across pregnancy is critical to children’s health. This work does not reflect US EPA policy.