Locomotor deficiencies and aberrant development of subtype-specific GABAergic interneurons caused by an unliganded thyroid hormone receptor alpha1.

Thyroid hormone (TH) deficiency during development causes severe and permanent neuronal damage, but the primary insult at the tissue level has remained unsolved. We have defined locomotor deficiencies in mice caused by a mutant thyroid hormone receptor alpha1 (TR alpha1) with potent aporeceptor activity attributable to reduced affinity to TH. This allowed identification of distinct functions that required either maternal supply of TH during early embryonic development or sufficient innate levels of hormone during late fetal development. In both instances, continued exposure to high levels of TH after birth and throughout life was needed. The hormonal dependencies correlated with severely delayed appearance of parvalbumin-immunoreactive GABAergic interneurons and increased numbers of calretinin-immunoreactive cells in the neocortex. This resulted in reduced numbers of fast spiking interneurons and defects in cortical network activity. The identification of locomotor deficiencies caused by insufficient supply of TH during fetal/perinatal development and their correlation with subtype-specific interneurons suggest a previously unknown basis for the neuronal consequences of endemic cretinism and untreated congenital hypothyroidism, and specifies TR alpha1 as the receptor isoform mediating these effects.

Neonatal iodine deficiency: clinical aspects.

Iodine is a trace element which is essential for the synthesis of thyroid hormones. The thyroid hormones, thyroxine (T4) and 3,5,3'-triiodothyronine (T3), are necessary for adequate growth and development throughout fetal and extrauterine life. The iodine intake of newborns is entirely dependent on the iodine content of breast milk and the formula preparations used to feed them. An inadequate iodine supply might be especially dangerous in the case of premature babies. The minimum recommended dietary allowance (RDA) for different age groups has recently been revised. The iodine intake required is at least 15 microg/kg/day in full-term infants and 30 microg/kg/day in preterms. The iodine content of many evaluated preparations for feeding premature infants appears to be inadequate. Premature infants are now in a situation of iodine deficiency, precisely at a stage of psychomotor and neural development which is extremely sensitive to alterations of thyroid function.

Hypothyroidism alters the development of radial glial cells in the term fetal and postnatal neocortex of the rat.

Alterations of thyroid function during human development are known to produce extensive damage to the central nervous system including severe mental retardation. Using immunohistochemistry to identify the intermediate filament nestin, we have studied the possible influence of fetal and neonatal hypothyroidism on neocortical neuronal migration by arresting the normal development of the radial glial scaffold. By embryonic day 21 (E21), hypothyroid animals had a significant decrease in the number of nestin immunoreactive processes in the presumptive visual cortex. By postnatal day 5 (P5), hypothyroid animals showed a significant increase in the number of glial processes in relation with controls, although only in the upper layers of the visual cortex. Moreover, by P10, there was a marked increase in the number of radial glial processes in hypothyroid animals in superficial and deep zones of the visual cortex with respect to control animals. Our data indicate an important delay in the formation of the radial glial scaffold during the embryonic stage in hypothyroid animals that was interestingly accompanied by the later presence of abundant nestin immunoreactive fibers at P10. This impairment in the evolution of radial glia during development might be affecting the normal neuronal migratory pattern in the neocortex of hypothyroid rats.