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.

Keywords: MCT8; brain; brain barriers; neurodevelopment; rodents; thyroid hormones; type 2 deiodinase.

Figure 1

Ontogenesis of thyroid hormone action during fetal brain development in the rat. In the rat brain, thyroid hormone receptors (TRs) mRNA expression is detected from E11.5 and TRs from E14. D2 activity in addition to 3,5,3′,5′-tetraiodo-L-thyronine (T4) and 3,5,3′-triodo-L-thyronine (T3) content are present in the rat fetal brain from at least E17 when the onset of fetal thyroid function takes place. D2 activity, T4 and T3 content progressively increase in the rat fetal brain from E17 until E21. The size of the figures does not represent relative abundance. Most of these events remain to be fully elucidated in the mouse.

Figure 2

Proposed model of T3 availability to the mouse developing brain. T4 mostly of maternal origin reaches the brain, gets transported into the cerebrospinal fluid and converted into T3 by D2 (in red) at the blood-cerebrospinal fluid barrier (meninges and choroid plexus) and at the lateral ventricles. From the cerebrospinal fluid the T3 could spread throughout the brain and access the neural cells to exert its action. CFS, cerebrospinal fluid; chp, choroid plexus; LV, lateral ventricles and mng, meninges.