Thyroid Hormone Availability and Action during Brain Development in Rodents

Abstract

Thyroid hormones (THs) play an essential role in the development of all vertebrates; in particular adequate TH content is crucial for proper neurodevelopment. TH availability and action in the brain are precisely regulated by several mechanisms, including the secretion of THs by the thyroid gland, the transport of THs to the brain and neural cells, THs activation and inactivation by the metabolic enzymes deiodinases and, in the fetus, transplacental passage of maternal THs. Although these mechanisms have been extensively studied in rats, in the last decade, models of genetically modified mice have been more frequently used to understand the role of the main proteins involved in TH signaling in health and disease. Despite this, there is little knowledge about the mechanisms underlying THs availability in the mouse brain. This mini-review article gathers information from findings in rats, and the latest findings in mice regarding the ontogeny of TH action and the sources of THs to the brain, with special focus on neurodevelopmental stages. Unraveling TH economy and action in the mouse brain may help to better understand the physiology and pathophysiology of TH signaling in brain and may contribute to addressing the neurological alterations due to hypo and hyperthyroidism and TH resistance syndromes.

Regulation of T3 Availability in the Developing Brain: The Mouse Genetics Contribution

“…Even after the onset of the fetal thyroid gland function, 60% of the total TH content in fetal peripheral tissues remains of maternal origin at late gestation stages in mice ( 43 ). In addition, there are good indications supporting the view that the main source of T3 in the fetal brain is maternal T4, not maternal T3.…”

“…As the concentration of T4 in the maternal serum exceeds that of T3, the net result is a preferential transfer of maternal T4 to the fetal serum ( 49 ). Furthermore, during fetal development, the contribution of fetal circulating T3 to brain T3 appears to be very low, suggesting that T3 is unable to cross the blood–brain barrier at this early stage ( 43 ). The collective term “blood–brain barrier” encompasses three putative pathways for TH entry in the brain: the blood–brain barrier proper, the blood–cerebrospinal fluid barrier, and the cerebrospinal fluid–brain barrier.…”

“…T4 is locally converted into T3 by DIO2, which is expressed in the brain ventricles as early as GD15 ( 50 ). By contrast, after birth, the fraction of brain T3 directly coming from the circulation reaches 50% ( 43 ).…”

“…Indeed, at mid-gestation, the level of T3 in the fetal brain is higher than in the fetal serum or liver ( 51 ). Under low levels of maternal T4, fetal T4 levels are decreased in peripheral organs and in the brain, but brain T3 level remains unchanged ( 43 ).…”

“…It is now recognized that specific transporters are needed for TH to cross the placenta, the blood–brain barrier or the blood–cerebrospinal fluid barrier ( 43 , 60 ). Intracytoplasmic transporters are also needed for T3 to reach cell nuclei ( 61 ).…”