Thyroid and Brain: Understanding the Actions of Thyroid Hormones in Brain Development and Function

This chapter is a general introduction to this book and contains basic concepts of thyroid hormone signaling for a better understanding of the book’s subject. It begins with an introduction that offers a simplified view of thyroid hormones as iodine-containing compounds and the regulatory function of the hypothalamuspituitary-thyroid axis, followed by a description of the thyroid gland and thyroid hormone synthesis. Iodide transporters concentrate iodide in the gland and after oxidation, it is incorporated into thyroglobulin tyrosyl residues. The coupling of iodotyrosyl residues forms T4 and T3, which are released after thyroglobulin hydrolysis. Thyroid hormones act via nuclear receptors, which are ligand-regulated transcription factors, and T3 is the primary active thyroid hormone that binds to the receptors. T3 is produced primarily in extrathyroidal tissues by the action of deiodinase enzymes catalyzing the removal of an iodine atom from T4. Thyroid hormones are ancient signaling molecules with critical actions on growth and metabolism that regulate many developmental transitions, with evolutionary roots at the base of the chordate species.

Congenital hypothyroidism is a thyroid hormone deficiency disorder present at birth due to thyroid gland failure. There are two types: primary and central. Primary congenital hypothyroidism is caused by either developmental disorders of the thyroid gland or defects in thyroid hormone synthesis. The central type, which is much less common, is caused by decreased TSH secretion or bioactivity. Thyroid dysgenesis and dyshormonogenesis are the major causes of congenital hypothyroidism. Most cases are multifactorial, involving several genes, and a small percentage is monogenic. Thyroid failure occurs prenatally, but maternal thyroid hormones may prevent fetal hypothyroidism and protect the brain. Untreated congenital hypothyroidism severely affects postnatal development, but neonatal screening allows for early thyroid hormone treatment, effectively preventing hypothyroidism. 

 Deiodinases (DIO) are central to regulating thyroid hormone action in the brain because they control the tissue concentration of the active hormone triiodothyronine (T3). DIO2, the outer ring, 5’-deiodinase expressed in the brain, converts T4 to T3 and is active primarily in two glial cell types: astrocytes and tanycytes. Astrocytes produce all of brain T3 during the fetal period and a significant fraction in adults. T3 from astrocytes reaches other neural cells, mainly neurons, devoid of DIO2. The T3 produced in the tanycytes travels to hypothalamic nuclei to perform neuroendocrine functions. DIO2 is expressed in the human fetal brain’s neural stem cells, known as outer radial glia. The inner ring, 5-deiodinase DIO3, converts T4 and T3 to the inactive compounds reverse T3 (rT3) and 3,3’T2, respectively, a reaction equivalent to suppressing thyroid hormone action. Brain DIO3 is active mainly in neurons. Thyroid hormones regulate the gene expression and enzymatic activity of DIO2 and DIO3. When T4 concentrations rise, DIO2 activity falls, and when T4 goes down, DIO2 increases. T3 stimulates the DIO3 gene, and DIO3 activity increases when T3 increases. The combined actions of DIO2 and DIO3 exert a “homeostatic-like mechanism” to maintain locally appropriate bioactivity of thyroid hormone by providing individual brain cells with the optimal concentrations of T3 required at different stages of development. These mechanisms regulate thyroid hormone action with a timeline specific to different brain regions.

Over the past four decades, a substantial body of evidence has emerged demonstrating the permeability of the placenta to thyroid hormones. Maternal thyroid hormones cross the placental barrier, becoming present in embryonic tissues well before the onset of thyroid gland function in both rodents and humans. This raises a fundamental question regarding the extent to which certain early developmental processes rely on maternal hormonal influence. While this concept is firmly supported by robust experimental data in rodents, the situation in humans is more nuanced. Numerous clinical observations suggest that a reduction in T4 levels in the blood of otherwise euthyroid pregnant women, a condition known as hypothyroxinemia, may have adverse effects on fetal development. However, clinical trials aimed at assessing the impact of treating maternal hypothyroxinemia with T4 have yielded disappointing results thus far, leaving the matter unresolved.

Iodine is an essential component of thyroid hormones, and its deficiency causes endemic goiter, cretinism, and a constellation of syndromes known as iodine deficiency disorders. Although iodine deficiency still affects most of the world, national or regional salt iodization programs have increased the number of countries with adequate intake. Endemic cretins were classified as either predominantly neurological or myxedematous (hypothyroid). Severe maternal iodine deficiency causes fetal neurological damage during the first half of gestation, which is prevented by administering iodine to mothers before or early in pregnancy. Myxedematous cretins present thyroid atrophy, hypothyroidism, and growth arrest, and no neurological involvement. Physiological adaptations to iodine deficiency include thyroid growth (goiter) and thyroidal autoregulatory mechanisms leading to decreased serum T4 and preserved serum T3. This situation is known as hypothyroxinemia, as described in Chapter 4. The brain, which depends on the T3 generated locally, shows an increased type 2 deiodinase activity and T3 formation from T4. When iodine intake is severe, these mechanisms cannot maintain T3 concentrations in the brain, leading to brain damage.

Thyroid hormones require transporter proteins that facilitate their influx and efflux through the cellular plasma membranes. There are many families of thyroid hormone transporter proteins, most of which transport other substrates, including bile acids, amino acids, monocarboxylates, and organic anions. The only transporter specific for thyroid hormones is the monocarboxylate 8 transporter or MCT8. MCT8 is present in the brain barriers and the membranes of neural cells. MCT8 mutations cause the Allan-Herndon-Dudley syndrome, described in the next chapter. Besides MCT8, the amino acid transporters LAT1 and LAT2 might have a physiological role in T4 and T3 transport. The organic anion transporter polypeptide 1C1 or OATP1C1 is a T4 transporter present in the mouse, but not the human, blood-brain barrier, and facilitates T4 transport to astrocytes and radial glia expressing type 2 deiodinase. A neurodegenerative disorder in a patient has been attributed to an OATP1C1 mutation. This chapter describes the physiological aspects of thyroid hormone transport across the different transporter families.

Mutations of the thyroid hormone cell-transporter gene, monocarboxylate transporter 8, or MCT8, cause an X-linked syndrome characterized by altered thyroid hormone concentrations in serum, profound neuromotor impairment, and cognitive deficits. This chapter describes the clinical features of the syndrome and analyzes the mechanisms of disease from studies of MCT8 deficiency in mice. The final section of the chapter describes the available treatments and experimental therapies.

The thyroid hormone receptors, encoded by the THRA and THRB genes, transduce the actions of T3. Receptor expression analysis gave clues on thyroid hormone and receptor functions in specific brain regions or cell types. This chapter describes the studies performed on rodents on receptor expression by various methodologies, including in situ hybridization and the phenotype of Thra and Thrb knockout mice. Most brain regions express the receptors from fetal stages. Receptor expression studies on rodents indicate that thyroid hormones regulate neuronal migration and differentiation during neocortical and cerebellar development. Given the critical role of thyroid hormones in brain development, it was expected that disruption of the receptor genes would be equivalent to hormone deprivation. However, in many cases, this is not so, raising the question of the role of unliganded receptor activity in hypothyroidism. This chapter ends with the few available data on receptor expression in the human fetal brain. 

Thyroid hormone receptor mutations cause syndromes of resistance to the action of thyroid hormones (RTH) with autosomal dominant inheritance. Mutations in the THRA gene, encoding TRα1 and TRα2, cause RTHα, and those in THRB, encoding TRβ1 and TRβ2, cause RTHβ. In RTHα, relatively mild changes in circulating thyroid hormones coexist with signs of congenital hypothyroidism. In contrast, in RTHβ, TSH levels are not suppressed despite elevated thyroid hormone levels. The mutant receptors have low or no T3-induced activation and display dominant negative activity, inhibiting the wild-type receptors’ transcriptional activation. This chapter describes the main characteristics of RTH, including a discussion of the mouse models of the disorder, with an emphasis on neural aspects.

Thyroid hormone exerts its actions by binding to nuclear receptors and regulating gene expression. Gene expression regulation by thyroid hormone in the brain is highly complex, with thousands of genes under the direct or indirect influence of T3. Adding to the complexity, gene dependence of T3 is age- and region-dependent, with diverse time window sensitivity. The maximal gene expression responses to T3 in rodents extend from the last 2-3 days of fetal life to the end of the first month, peaking around postnatal days 15-21. T3 regulates genes involved in almost all aspects of brain function, from developmental genes to genes involved in metabolic and cell signaling pathways. In most cases, the effect of T3 is to fine-tune the relative abundance of selected gene products at the right time and place, promoting maturational processes during developmental transitions.

The control of myelination in the central nervous system is a classical action of thyroid hormones. In rodents, thyroid hormone deficiency during the fetal and postnatal periods delays central myelin deposition and oligodendrocyte gene expression. Oligodendrocytes differentiate from precursor cells (OPC), originating from radial glial cells in the ventricular and subventricular zones after multiple cell fate decisions controlled by developmental genes. The interplay between growth factors acting at the cell membranes and nuclear receptors, such as those for T3 and retinoic acid, regulates OPC differentiation. Growth factors promote OPC proliferation, and the liganded nuclear receptors promote cell cycle exit. Myelination occurs in axons that reach a critical size, and thyroid hormone might also indirectly affect myelination through axonal maturation effects. In the clinical setting, myelination can be analyzed by magnetic resonance imaging in hypothyroid states with variable results.

This chapter provides a comprehensive exploration of the role of thyroid hormones in the development of key brain structures: the cerebral cortex, hippocampus, striatum, and cerebellum, as well as the sense organs retina and cochlea. Hypothyroidism is generally associated with impairments in axodendritic development, synaptogenesis, neuron migration and differentiation, and myelination. In the developing cerebral cortex, hypothyroidism delays the appearance of Cajal-Retzius cells, critical for the proper migration of neurons, causing migration defects. The maturation of the transient subplate layer, crucial for establishing thalamocortical connections, is also delayed. The hippocampal formation experiences a reduction in the number of granular cells and mossy fibers. In the cerebellum, hypothyroidism arrests the maturation of the Purkinje cells and delays the migration of the granular cells to the internal granular layer. In the striatum, hypothyroidism delays the accumulation of the medium-spiny GABAergic neurons, the principal cells of the striatum. Parvalbumin interneurons in the cerebral and cerebellar cortices are also affected. Thyroid hormone induces extensive remodeling during cochlear and retinal maturation. Contrary to expectations, receptor-deficient mice often do not exhibit these alterations, while the expression of mutant receptors with impaired T3 binding results in hypothyroid features. In rodents, the effects of thyroid hormones are most prominent during the postnatal period. Conversely, in humans, the second trimester of pregnancy is a crucial period for neural development. The coordinated development of the thyroid hormone signaling system, encompassing brain T3 and the ontogenesis of receptors, deiodinases, and regulated genes, closely aligns with late maturational processes. This intricate interplay underscores the significance of thyroid hormones in shaping the structural and functional aspects of the developing brain.

In adult mammals, neurogenesis persists throughout life in two active sites: the ventricular-subventricular zone along the lateral ventricles and the subgranular zone of the hippocampus. In rodents, postnatal neural stem cells with astrocytic properties, originating from embryonic ventricular radial glia, generate a continuous, lifelong supply of neurons for the olfactory bulb and glia for the corpus callosum. Thyroid hormones play a regulatory role in this process. In humans, ventricular neurogenesis is minimal, but hippocampal neurogenesis extensively remodels the dentate gyrus, influencing memory and mood. Hippocampal neurogenesis begins with stem cells in the dentate gyrus subgranular layer, generating a sequential lineage of intermediate precursors and neuroblasts. These neuroblasts migrate to the granular layer, differentiate into granular cells, and integrate into the existing dentate gyrus neuronal pool. Thyroid hormone specifically regulates the late stages of this process, promoting the terminal differentiation of neuroblasts and facilitating their functional integration. Hypothyroidism disrupts hippocampal neurogenesis, impacting learning, memory, and mood. The intricate regulation of adult neurogenesis by thyroid hormone highlights their crucial role in maintaining cognitive and emotional functions.

Thyroid hormone deficiency or excess may cause emotional disturbances and mood disorders, encompassing major depressive syndromes and bipolar disorders, along with various other neuropsychiatric conditions, some of which may have developmental origins. In particular, profound long-term untreated hypothyroidism can culminate in severe psychosis, historically referred to as myxedema madness. Addressing the underlying thyroid condition typically proves highly effective in rectifying the associated brain disorder. Subclinical thyroid diseases have also been implicated in emotional and cognitive disorders, prompting inquiry into the optimal treatment window. Moreover, thyroid hormones have demonstrated potential in expediting or augmenting the effects of standard mood disorder treatments in euthyroid patients, hinting at a baseline state of localized cerebral hypothyroidism with an uncertain pathogenesis, potentially remediable through high doses of thyroid hormones.