Please cite this article in press as: Gilbert ME, Lasley SM. Developmental thyroid hormone insufficiency and brain development: A role for brain-derived neu- rotrophic factor (BDNF)? Neuroscience (2013), http://dx.doi.org/10.1016/j.neuroscience.2012.11.022 Neuroscience xxx (2013) xxx–xxx REVIEW DEVELOPMENTAL THYROID HORMONE INSUFFICIENCY AND BRAIN DEVELOPMENT: A ROLE FOR BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF)? M. E. GILBERT a* AND S. M. LASLEY b the available literature, the case for a direct role for BDNF a Toxicity Assessment Division, Neurotoxicology Branch, U.S. in thyroid-mediated effects in the brain is not compelling. Environmental Protection Agency, Research Triangle Park, NC, USA We conclude that delineation of the potential role of neuro- trophins in TH-mediated neuronal development may be b Department of Cancer Biology and Pharmacology, University more fruitful by examining additional neurotrophins (e.g., of Illinois College of Medicine, Peoria, IL, USA nerve growth factor), moderate degrees of TH insufficiency, and younger ages. We further suggest that investigation of Abstract—Thyroid hormones (TH) are essential for normal BDNF invoked by synaptic activation (i.e., plasticity, enrich- brain development. Even modest degrees of TH disruption ment, trauma) may serve to elucidate a role of thyroid experienced in utero can result in neuropsychological defi- hormone in BDNF-regulated synaptic function. cits in children despite normal thyroid status at birth. Neuro- This article is part of a Special Issue entitled: Steroid hor- trophins have been implicated in a host of brain cellular mones and BDNF. Published by Elsevier Ltd. on behalf of functions, and in particular, brain-derived neurotrophic IBRO. factor (BDNF) has a well documented role in development and function of the nervous system. A number of laborato- Key words: BDNF, hypothyroidism, hippocampus, cortex, ries have reported the effects of TH administration or severe developmental, propylthiouracil. deprivation on neurotrophin expression in brain. This review provides an overview and update of recent develop- ments in the thyroid field as they relate to the nervous Contents system. Secondly, we describe an animal model of low level Introduction 00 TH insufficiency that is more relevant for studying the Some basics of thyroid biology 00 neurological consequences associated with the modest TH Thyroid hormone transporters in the brain 00 perturbations of subclinical hypothyroidism, or that would Thyroid hormone metabolism in the brain 00 be anticipated from exposure to environmental contami- Non-genomic actions and novel thyroid signaling molecules 00 nants with a mode-of-action that involves the thyroid. Effects of TH insufficiency in humans 00 Finally, we review the available in vivo literature on TH-med- Environmental factors and subclinical hypothyroidism 00 iated alterations in neurotrophins, particularly BDNF, and Pharmacological models of hypothyroidism using propylthio- discuss their possible contribution to brain impairments uracil and methimazole 00 associated with TH insufficiency. The observations of Low dose PTU model characterization 00 altered BDNF protein and gene expression have varied as Hippocampal synaptic transmission and plasticity 00 a function of hypothyroid model, age, and brain region Hippocampal-dependent learning 00 assessed. Only a handful of studies have investigated the Cell fate specificity and white matter abnormalities 00 relationship of neurotrophins and TH using models of TH Errors in neuronal migration 00 deprivation that are not severe, and dose–response informa- Is there a role for neurotrophins in the developmental effects of tion is sparse. Differences in the models used, species, thyroid hormone insufficiency? 00 doses, regions assessed, age at assessment, and method Increasing thyroid hormones in adults in vivo 00 employed make it difficult to reach a consensus. Based on Augmenting thyroid hormones in the neonate in vivo 00 Reducing thyroid hormones in the adult 00 Reducing thyroid hormones to neonate 00 *Corresponding author. Address: Toxicity Assessment Division, Summary and conclusions 00 Neurotoxicology Branch (MD-B105-05), National Health and Envi- Uncited reference 00 ronmental Effects Research Laboratory, U.S. Environmental Protec- Acknowledgments 00 tion Agency, Research Triangle Park, NC 27711, USA. Tel: +1-919- References 00 541-4394; fax: +1-919-541-4849. E-mail address: [email protected] (M. E. Gilbert). Abbreviations: BDNF, brain-derived neurotrophic factor; GD, gestational day; GFAP, glial fibrillary acidic protein; LTP, long-term potentiation; MCT, monocarboxylate transporter; MMI, methimazole; NGF, nerve growth factor; NT, neurotrophin; OATP, organic anion- INTRODUCTION transporting polypeptide; PTU, propylthiouracil; T1AM, 3- iodothyronamine; T3, 3,5,30-triiodothyronine; T4, thyroxine; TH, thyroid hormones; TRE, thyroid response element; TSH, thyroid Thyroid hormones (TH) are critical for normal on brain stimulating hormone. development. Severe TH deficiencies in the neonatal 0306-4522/12 $36.00 Published by Elsevier Ltd. on behalf of IBRO. http://dx.doi.org/10.1016/j.neuroscience.2012.11.022 1 2 M. E. Gilbert, S. M. Lasley / Neuroscience xxx (2013) xxx–xxx period are of clinical interest because they can result in is distinct from, and impairments more subtle than, those diminished mental capacity which can be mitigated with resulting from chemical or surgical thyroidectomy. early diagnosis and hormone supplementation. However, It is the TRE, not the liganded receptor, which directly a greater recognition of the impact of maternal regulates specific TH-responsive genes. Few genes have subclinical hypothyroidism on fetal CNS function is been identified that are directly activated by TH, and of emerging, and the contribution of TH-disrupting that group, most are transcription factors (e.g., hairless, environmental contaminants in this etiology remains to hr) that modulate the expression of other genes be determined. Because of the established roles of (Thompson and Potter, 2000). TH regulation of these neurotrophins in neuronal migration, differentiation, and downstream genes is therefore indirect as these genes plasticity, there has been a focus of efforts to understand do not themselves possess a TRE and do not bind the their role in TH-mediated neurological effects. T3-receptor complex. In this manner TH can modulate In this review we examined the available literature to the expression of a multitude of downstream genes, an evaluate the association between TH disruption and action that dramatically increases the sphere of their neurotrophin gene/protein expression. TH synthesis influence on brain development, as well as the difficulty inhibitors have been used to pharmacologically induce identifying developmentally important TH-responsive hypothyroidism in animals, and we review data genes (Anderson et al., 2003; Flamant and Samarut, generated by these models. The roles of neurotrophins, 2003; Quignodon et al., 2004). Furthermore, TRs do not with special attention to brain-derived neurotrophic regulate the same genes in all neuronal cell types, nor factor (BDNF), are then evaluated by examining their do they regulate the same gene in the same cell over responses to TH supplementation or deprivation in time during development, necessitating the existence of young and adult animals in vivo. This assessment of the mechanisms that control the cell specificity and timing of literature will allow us to define clearer roles for TH on TR action (Iniguez et al., 1996; Williams, 2008; neurotrophin function, to evaluate the potential for Hernandez et al., 2010). Selective expression of TH- neurotrophins to serve as biomarkers of developmental specific transporter proteins in the brain and local TH effects, and to elucidate the course of future studies. metabolizing enzymes represent two mechanisms whose relative contribution to the local fidelity of TH signaling is just beginning to be unravelled. SOME BASICS OF THYROID BIOLOGY Adding further to this complexity, the degree of change in the expression of TH-responsive genes in the brain is TH is essential for a number of physiological processes in subtle in nature, standing in marked contrast to TH- mammalian species. In the hypothalamic–pituitary– mediated change in gene expression in many other thyroid axis (HPTA), thyroid releasing hormone (TRH) tissues. Most known neural genes exhibit transient from the hypothalamus stimulates the pituitary to release responsiveness to TH and undergo changes in thyroid stimulating hormone (TSH). TSH acts on thyroid expression of only two to threefold in response to the gland receptors to activate synthesis and release of TH. hormone (Poguet et al., 2003; Quignodon et al., 2004; Thyroxine (T4) is the predominant form of TH released Royland et al., 2008). Consequently, it has proven into the bloodstream and is enzymatically deiodinated to challenging to associate the changes in expression of a 0 3,5,3 -triiodothyronine (T3), a high-affinity ligand for the particular gene or family of genes to the well known nuclear TH receptors TRa and TRb, whose activation effects of TH on brain development (Oppenheimer and regulates vertebrate development and physiology. In the Schwartz, 1997; Thompson and Potter, 2000; Bernal, circulation, these hormones are bound to serum proteins 2002). for transport and delivery to the many TH-dependent Difficulty linking alterations in gene expression and organs. The developing brain is one organ most brain function may also