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Neurodevelopmental malformations of the cerebellar vermis in genetically engineered rats
Ramos, R., S. Van Dine, M. Gilbert, J. Leheste, AND G. Torres. Neurodevelopmental malformations of the cerebellar vermis in genetically engineered rats. The Cerebellum. Springer International Publishing AG, Cham (ZG), Switzerland, 14(5):624-31, (2015).
The EPA must evaluate the risk of exposure of the developing organism to chemicals with the potential to disrupt thyroid hormone (TH) and for which the degree of hormone perturbation is likely to be fairly mild. THs are important for neuronal migration and the appropriate formation of neocortical and cerebellar lamina. We have recently documented mild subclinical T4 reduction in the pregnant dam is sufficient to induce a neuronal migration defect in the cortex of her offspring (Gilbert et al., 2014). The cerebellum is a posnatally developing brain structure whose normal function is required for both motor and cognitive skills and is a brain region that has also been shown, at severe hormone deficiencies, to exhibit malformations due to failed or delayed neuronal migration. The effects at lower levels of hormone perturbation have not been addressed. Because the cerebellum is particularly vulnerable to neurodevelopmental malformations in humans and rodents, with rodents exhibiting spontaneous cerebellar malformations, we propose that the alterations in cerebellar structure may represent a sensitive endpoint for detection of thyroid hormone perturbations during the early postnatal period. Investigation of subtle alterations in cerebellar structure would be greatly facilitated by use of genetically modified animals engineered as reporters for specific neuronal cell types.
The cerebellar vermis is particularly vulnerable to neurodevelopmental malformations in humans and rodents. Sprague-Dawley, and Long-Evans rats exhibit spontaneous cerebellar malformations consisting of heterotopic neurons and glia in the molecular layer of the vermis. Malformations are almost exclusively found along the primary fissure and are indicative of deficits of neuronal migration during cerebellar development. In the present report, we test the prediction that genetically engineered rats on Sprague-Dawley or Long-Evans backgrounds will also exhibit the same cerebellar malformations. Consistent with our hypothesis, we found that three different transgenic lines on two different backgrounds had cerebellar malformations.Heterotopia in transgenic rats had identical cytoarchitecture as that observed in wild-type rats including altered morphology of Bergmann glia. In light of the possibility that heterotopia could affect results from behavioral studies, these data suggest that histological analyses be performed in studies of cerebellar function or development when using genetically engineered rats on these backgrounds in order to have more careful interpretation of experimental findings.