Analysis of thyroid hormone-dependent genes in the brain by in situ hybridization.

Among the most dramatic actions of thyroid hormone are those exerted on brain development and function. In the adult human brain, a deficiency or excess of thyroid hormone may lead to various psychiatric manifestations, but it is during development when thyroid hormone exerts its most varied and critical actions on neural tissue. In humans, a deficiency of thyroid hormone taking place during a critical period of development may lead to severe mental retardation and also to neurological defects (1). This critical period may extend from the start of the second trimester of pregnancy to the first few months after birth. During this period, the absence of thyroid hormone, if not corrected by early postnatal treatment, leads to irreversible damage with mental retardation. While in utero, the fetal brain is protected from thyroid deficiency by the maternal hormone. Severe thyroid hormone deficiency in the pregnant woman, especially if combined with fetal deficiency, leads to severe neurological deficits in the child that are irreversible even with early postnatal treatment. In the most studied model of thyroid hormone deficiency, the severely hypothyroid rat, there are no gross alterations of brain morphology. However, there are defects of myelination, alterations of cell migration in the cerebral cortex and the cerebellum, and abnormal differentiation of many neurons, including cholinergic cells and cerebellar Purkinje cells, with severe functional consequences (2). Elucidation of the molecular basis of thyroid hormone action in the brain is important because it may help to understand how epigenetic factors modify the