Sustained production of Reelin-expressing interneurons in the hippocampal dentate hilus after developmental exposure to anti-thyroid agents in rats.

To detect molecular evidence reflecting a permanent disruption of neuronal development due to hypothyroidism, distribution of Reelin-producing cells that function in neuronal migration and positioning was analyzed in the hippocampal dentate hilus using rats. From gestation day 10, maternal rats were administered either 6-propyl-2-thiouracil (PTU) at 3 or 12ppm (0.57 or 1.97mg/kg body weight/day) or methimazole (MMI) at 200ppm (27.2mg/kg body weight/day) in the drinking water and male offspring were immunohistochemically examined at the end of exposure on weaning (postnatal day 20) and at the adult stage (11-week-old). Offspring with MMI and 12ppm PTU displayed evidence of growth retardation lasting into the adult stage. On the other hand, all exposure groups showed a sustained increase in Reelin-expressing cells in the dentate hilus until the adult stage in parallel with Calbindin-D-28K-expressing cells at weaning and with glutamic acid decarboxylase 67-positive cells in the adult stage, confirming an increase in gamma-aminobutyric acid (GABA)ergic interneurons. At the adult stage, NeuN-positive postmitotic mature neurons were also increased in the hilus in all exposure groups, however, the increased population of Reelin-producing cells at this stage was either weakly positive or negative for NeuN, indicative of immature neurons. At weaning, neuroblast-producing subgranular zone of the dentate gyrus showed increased apoptosis and decreased cell proliferation suggestive of impaired neurogenesis. The results suggest that sustained increases of immature GABAergic interneurons synthesizing Reelin in the hilus could be a signature of compensatory regulation for impaired neurogenesis and mismigration during the neuronal development as a hypothyroidism-related brain effect rather than that secondary to systemic growth retardation.