Lower Thyroid Compensatory Reserve of Rat Pups after Maternal Hypothyroidism: Correlation of Thyroid, Hepatic, and Cerebrocortical Biomarkers with Hippocampal Neurophysiology

Abstract

The developing central nervous system of the fetus and neonate is recognized as very sensitive to maternal or gestational hypothyroidism. Despite this recognition, there is still a lack of data concerning the relationship between thyroid-related biomarkers and neurological outcomes. We used propylthiouracil administered at 0, 3, or 10 ppm in drinking water from gestational d 2 until weaning to create hypothyroid conditions to study the relationship between hypothalamic-pituitary-thyroid axis compensation and impaired neurodevelopment. In addition to serum T(3), T(4), free T(4), and TSH concentrations, cerebrocortical T(3) concentration (cT(3)), hepatic type I and cerebrocortical type II (D2) 5'-deiodinase activity, and thyroidal mRNA for thyroglobulin and sodium iodide symporter were measured. Extracellular recordings from the CA1 region in hippocampal slices were obtained from both postnatal d 21-32 (pups) and postnatal d 90-110 (adults) rats to assess neurophysiological effects. Thyroidal mRNA for thyroglobulin and sodium iodide symporter were increased in pups but not in dams. Both propylthiouracil doses increased cerebrocortical D2 activity approximately 5-fold in pups but only 10 ppm increased D2 activity in dams. In dams, cT(3) concentrations were maintained at 3 ppm but fell 75% at 10 ppm. cT(3) concentration in pups fell 50% at 3 ppm and more than 90% at 10 ppm. In both 3 and 10 ppm pups, hippocampal baseline synaptic activity correlated negatively with cerebrocortical D2 activity. In 3 ppm adults, impaired long-term potentiation was evident. In summary, during depletion of serum T(4), D2 activity served as a sensitive marker of tissue thyroid status, an indicator of the brain's compensatory response to maintain cT(3), and correlated with a neurophysiological outcome.