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Modest Thyroid Hormone Insufficiency during Development Induces a Cellular Malformation in the Corpus Callosum: A Model of Cortical Dysplasia

Center for Neural Recovery and Rehabilitation Research (J.H.G.), Helen Hayes Hospital, West Haverstraw, New York 10993; Neurotoxicology Division (M.E.G.), U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711; and Department of Psychology (M.E.G.), University of North Carolina, Chapel Hill, North Carolina 27599

Address all correspondence and requests for reprints to: Jeffrey H. Goodman, Ph.D., Center for Neural Recovery and Rehabilitation Research, Helen Hayes Hospital, West Haverstraw, New York 10993. E-mail: j.goodman{at}juno.com.

There is a growing body of evidence that subtle decreases in maternal thyroid hormone during gestation can impact fetal brain development. The present study examined the impact of graded levels of thyroid hormone insufficiency on brain development in rodents. Maternal thyroid hormone insufficiency was induced by exposing timed-pregnant dams to propylthiouracil (PTU) at doses of 0, 1, 2, 3, and 10 ppm in the drinking water from gestational d 6 through weaning on postnatal d 30. An examination of Nissl-stained sections of the brains from developmentally hypothyroid offspring killed on postnatal d 23 revealed the presence of a heretofore unreported bilateral cellular malformation, a heterotopia, positioned within the white matter of the corpus callosum of both hemispheres. Immunohistochemical techniques were used to determine that this heterotopia primarily consists of neurons born between gestational d 17–19 and exhibits a dose-dependent increase in size with decreases in thyroid hormone levels. Importantly, this structural abnormality is evident at modest levels of maternal thyroid hormone insufficiency (45% reductions in T₄ with no change in T₃), persists in adult offspring despite a return to normal hormonal status, and is dramatically reduced in size with prenatal thyroid hormone replacement. Developmental exposure to methimazole, another goitrogen, also induced formation of this heterotopia. Whereas the long-term consequence of this cortical malformation on brain function remains to be determined, the presence of the heterotopia underscores the critical role thyroid hormone plays in brain development during the prenatal period and provides a new model in which to study mechanisms of cortical development and cortical dysplasia.

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