Thyroid hormones (T3, T4) play a critical but only partially understood role in the development and maintenance of normal peripheral and central nervous system function, behavior, and learning. Mental retardation, learning disability, and neurological and psychiatric abnormalities including delirium, dementia, psychosis, and paranoid ideation, and depression have been reported with hyper or hypo-thyroidism. Deficiency of thyroid hormone during intrauterine life underlies the syndrome of congenital hypothyroidism, which is a cause of mental retardation, impaired learning, motor disability, deafness, and blindness. The syndrome of congenital hypothyroidism occurs in 1 in 5000 births. The cognitive, neurological and psychiatric manifestations may be related to thyroid mediated changes in developing brain gene expression. For our understanding of the pathophysiology and treatment of the human condition, an animal model of congenital hypothyroidism is essential. The general purpose of the present proposed series of studies is to utilize an interdisciplinary approach to determine the utility of an inbred mouse animal model of mental retardation, the hyt-hyt congenitally hypothyroid mouse and to use this model to elucidate the mechanism of thyroid hormone control of specific brain gene expression. This model may help us learn more about the molecular biological basis of behavior, the treatment, etiology, and substrate of mental retardation as well as the initial and pervasive effects of thyroid hormones on the developing brain.
The specific aims are: 1) To further characterize the behavioral, and learning differences that exist in the hyt/hyt hypothyroid mouse fetus, neonate and young adult relative to normal mouse offspring. 2) To quantitate several mouse mRNAs including IGF-1 and EGF which are regulated by thyroid hormones during the intrauterine period following the onset of fetal mouse thyroid function (14 to 19 days of gestation). 3) To quantitate in cerebral cortex and characterize the thyroid hormone regulated brain mRNAs in normal and hyt/hyt mice. 4) To try to localize and quantify these thyroid hormone regulated cerebral cortex mRNAs in specific cell groups in cerebral cortex layers III-IV by in situ hybridization. 5) To correlate the behavioral, neuroanatomical, and molecular biology results.
