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DEVELOPMENTAL HYPOTHYROIDISM INDUCES A NEURONAL HETEROTOPIA IN THE CORPUS CALLOSUM OF THE RAT.
Citation:
GOODMAN, J. AND M. E. GILBERT. DEVELOPMENTAL HYPOTHYROIDISM INDUCES A NEURONAL HETEROTOPIA IN THE CORPUS CALLOSUM OF THE RAT. Presented at 13th International Thyroid Congress, Buenos Aires, ARGENTINA, October 30 - November 04, 2005.
Description:
It is well established that severe hypothyroidism leads to profound alterations in brain development and mental retardation. In this study we examined the effect of subtle decreases in maternal thyroid hormones (TH) on brain development in the rat. To induce TH insufficiency pregnant rats received propylthiouracil (PTU) in the drinking water (0, 3, 10ppm) from gestational day (GD6) until the pups were weaned on postnatal day (PN) 30. On PN23 and PN86 the progeny were anesthetized and perfusion-fixed with 4% paraformaldehyde and the brains were prepared for immunohistochemistry. Nissl-stained sections revealed a bilateral cellular malformation, a heterotopia (HT), within the corpus callosum of PTU exposed rats (3ppm - 7/8; 10ppm -15/15) that was never observed in control rats (0/8). The size of the HT was dependent on the degree of TH deprivation, ranging 50-800m in 3ppm and 350-1300m in 10ppm-treated rats in the rostral-caudal plane. The HT was still present in PN86 rats (4/4 3ppm, 5/5 10ppm) despite the return to a euthyroid state. Immunohistochemistry for NeuN, a neuron-specific marker revealed the bulk of cells within the HT to be neurons. In a separate cross-fostering study the HT was present in rats made hypothyroid prenatally but not in rats made hypothyroid postnatally indicating that development of the HT required prenatal TH insufficiency. The birth date of the neurons within the HT was determined by administration of bromodeoxyuridine (BrdU, 50mg/kg, ip) on GD14-16 or GD17-19 to dams exposed to PTU (0, 1, 3 and 10ppm). A HT was present in a proportion of pups born to dams with modest reductions in circulating TH (1 ppm PTU reduced T4 in dams by 25% without change in T3), and all offspring from the higher dose groups (3 and 10ppm). Immunostaining for BrdU revealed that cells within the HT were born after GD16. The impact of this malformation on brain function is yet to be determined. We postulate that early TH insufficiency may underlie some developmental disorders of childhood origin that stem from altered cell migration. (Does not reflect EPA policy).