Abstract
Cortical heterotopias are clusters of ectopic neurons in the brain and are associated with neurodevelopmental disorders like epilepsy and learning disabilities. We have previously characterized the robust penetrance of a heterotopia in a rat model, induced by thyroid hormone (TH) disruption during gestation. However, the specific mechanism by which maternal TH insufficiency results in this birth defect remains unknown. Here we first determined the developmental window susceptible to endocrine disruption and describe a cellular mechanism responsible for heterotopia 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. Beginning in the early postnatal brain, neurons begin to aggregate near the ventricles of treated animals. In parallel, transcriptional and architectural changes of this region were observed including decreased Sonic hedgehog (Shh) expression, abnormal cell adhesion, and altered radial glia morphology. As the ventricular epithelium is juxtaposed to two sources of brain THs, the cerebrospinal fluid and vasculature, this progenitor niche may be especially susceptible to TH disruption. This work highlights the spatiotemporal vulnerabilities of the developing brain and demonstrates that a transient period of TH perturbation is sufficient to induce a congenital abnormality.
Highlights
Normal brain development requires thyroid hormone (TH) during both pregnancy and the postnatal period in humans[1]
Results demonstrate that maternal PTU treatment from GD19-PN2, the perinatal period, is both sufficient and necessary to induce a cortical heterotopia in 100% of the offspring analyzed on PN14 (Fig. 1c, 10/10 animals, two littermates were assayed across five litters)
No animals from any other exposure possessed this birth defect, albeit pups born to dams treated with PTU from GD9-PN2, which represents the positive control treatment (Fig. 1c, 6/6 animals, two littermates were assayed across three litters)
Summary
Normal brain development requires thyroid hormone (TH) during both pregnancy and the postnatal period in humans[1]. Characterized as clusters of ectopic neurons within the corpus callosum, this permanent birth defect is observable in rat offspring born to both hypothyroid and TH insufficient dams This phenotype is present in offspring even when maternal thyroid stimulating hormone (TSH) is not significantly increased[13], an intriguing observation given that TSH is the benchmark measure for estimating TH dysfunction during human pregnancy. We postulate that insufficient adhesion at the apical surface of the ventricular epithelium compromises the normal attachment of radial glial end feet, leading to disorganization of the radial glial fibers This disruption of the migratory scaffolding promotes aggregation of neurons near the lateral ventricles, resulting in heterotopia. This work highlights the spatiotemporal susceptibilities of the developing central nervous system and suggests that the timing of TH insufficiency is a critical variable when interpreting the risk of TH disruption during pregnancy
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