Role of Late Maternal Thyroid Hormones in Cerebral Cortex Development: An Experimental Model for Human Prematurity

Abstract

Hypothyroxinemia affects 35–50% of neonates born prematurely (12% of births) and increases their risk of suffering neurodevelopmental alterations. We have developed an animal model to study the role of maternal thyroid hormones (THs) at the end of gestation on offspring's cerebral maturation. Pregnant rats were surgically thyroidectomized at embryonic day (E) 16 and infused with calcitonin and parathormone (late maternal hypothyroidism [LMH] rats). After birth, pups were nursed by normal rats. Pups born to LMH dams, thyroxine treated from E17 to postnatal day (P) 0, were also studied. In developing LMH pups, the cortical lamination was abnormal. At P40, heterotopic neurons were found in the subcortical white matter and in the hippocampal stratum oriens and alveus. The Zn-positive area of the stratum oriens of hippocampal CA3 was decreased by 41.5% showing altered mossy fibers’ organization. LMH pups showed delayed learning in parallel to decreased phosphorylated cAMP response element-binding protein (pCREB) and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) expression in the hippocampus. Thyroxine treatment of LMH dams reverted abnormalities. In conclusion, maternal THs are still essential for normal offspring's neurodevelopment even after onset of fetal thyroid function. Our data suggest that thyroxine treatment of premature neonates should be attempted to compensate for the interruption of the maternal supply.

Do children with congenital hypothyroidism exhibit abnormal cortical morphology?

“…This concurs with our finding that CH had thinning in the superior frontal gyrus and thickening in the middle frontal sulcus. Current findings are also consistent findings of local migration abnormalities in sensorimotor, auditory, and visuospatial cortices of TH-deprived rodents (11,23).…”

“…In other words, cortical thickening may represent a more juvenile pattern of brain development than seen in TDC. Additionally, some neurons failing to reach the cortical plate may have remained in lower layers or even the white matter, thus giving the appearance of an abnormally long-and hence thicker-cortex (11). Also, these migrational failures could lead to heterotopias, as observed in autism (25), which coincidentally is also associated with gestational TH insufficiency (26).…”

“…When TH is missing, fundamental neurobiological processes such as neurogenesis, neuronal migration, synaptogenesis, and myelination develop atypically (7), while structures such as hippocampus (8), striatum (9), and cortex (10,11) are abnormal. Within the cortex, a late gestational/early postnatal TH insufficiency is associated with disturbed corticogenesis due to abnormal asymmetric division of neurons migrating toward the cortical surface (12).…”

Understanding Prenatal Iodine Deficiency

“…2 These studies have shown changes in cerebellum with reductions in weight and cell number, and delayed maturation. The influence of maternal hypothyroxinemia on neocortical development has been recently studied in rats and mice.…”

“…Further, it is essential for the proper development and function of the Central Nervous System. 2 Since the first epidemiological studies conducted by Pharoah 3 and Thilly 4 in the 70's, the association between iodine deficiency in pregnant women and fetal neurological damage has been extensively reviewed and proven in scientific literature. In fact, the need to provide iodine supplementation to pregnant women in iodine-deficient regions is considered as proven by scientific evidence.…”