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Modest Thyroid Hormone Insufficiency during Development Induces a Cellular Malformation in the Corpus Callosum: A Model of Cortical Dysplasia

Center for Neural Recovery and Rehabilitation Research (J.H.G.), Helen Hayes Hospital, West Haverstraw, New York 10993; Neurotoxicology Division (M.E.G.), U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711; and Department of Psychology (M.E.G.), University of North Carolina, Chapel Hill, North Carolina 27599

Address all correspondence and requests for reprints to: Jeffrey H. Goodman, Ph.D., Center for Neural Recovery and Rehabilitation Research, Helen Hayes Hospital, West Haverstraw, New York 10993. E-mail: j.goodman{at}juno.com.

	Abstract

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There is a growing body of evidence that subtle decreases in maternal thyroid hormone during gestation can impact fetal brain development. The present study examined the impact of graded levels of thyroid hormone insufficiency on brain development in rodents. Maternal thyroid hormone insufficiency was induced by exposing timed-pregnant dams to propylthiouracil (PTU) at doses of 0, 1, 2, 3, and 10 ppm in the drinking water from gestational d 6 through weaning on postnatal d 30. An examination of Nissl-stained sections of the brains from developmentally hypothyroid offspring killed on postnatal d 23 revealed the presence of a heretofore unreported bilateral cellular malformation, a heterotopia, positioned within the white matter of the corpus callosum of both hemispheres. Immunohistochemical techniques were used to determine that this heterotopia primarily consists of neurons born between gestational d 17–19 and exhibits a dose-dependent increase in size with decreases in thyroid hormone levels. Importantly, this structural abnormality is evident at modest levels of maternal thyroid hormone insufficiency (45% reductions in T₄ with no change in T₃), persists in adult offspring despite a return to normal hormonal status, and is dramatically reduced in size with prenatal thyroid hormone replacement. Developmental exposure to methimazole, another goitrogen, also induced formation of this heterotopia. Whereas the long-term consequence of this cortical malformation on brain function remains to be determined, the presence of the heterotopia underscores the critical role thyroid hormone plays in brain development during the prenatal period and provides a new model in which to study mechanisms of cortical development and cortical dysplasia.

	Introduction

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WHEREAS IT IS well established that severe developmental hypothyroidism can cause profound alterations in brain development leading to neurological cretinism, it has only recently been recognized that subtle decreases in maternal thyroid hormone can alter fetal brain development (1, 2, 3). During the first half of gestation, before the onset of fetal thyroid function, the mother is the sole source of thyroid hormone for the developing fetus such that small decreases in maternal hormone levels have the potential to interfere with brain development. Clinically, impairments in neuropsychological development and intellectual function have been observed in children born to women with minor, subclinical thyroid disturbances (3, 4, 5).

In rodent models, developmental hypothyroidism interferes with neuronal migration, differentiation, and myelination in the neocortex and hippocampus (1, 6, 7, 8, 9), which is consistent with the observations that thyroid hormone regulates genes that control formation of the corpus callosum and neuronal migration (10, 11, 12, 13, 14). Moreover, gestational hypothyroidism also alters the development of radial glial cells, which are necessary for formation of the neocortex (14). Recent studies examining low-level thyroid hormone disruption during early brain development identified permanent structural alterations in the neocortex and hippocampus in the progeny of developmentally hypothyroxinemic and hypothyroid rats (1, 2, 8). These findings are particularly striking because the changes in cortical structure were observed in animals in which the degree of maternal hypothyroidism was small and the duration of the deficit was limited.

The present study examined the impact of graded levels of thyroid hormone insufficiency on brain development and describes the presence of a heretofore unreported bilateral malformation, a heterotopia, in the corpus callosum of developmentally hypothyroid rodents. This heterotopia is comprised of neurons, is consistently positioned within the white matter of the corpus callosum of both hemispheres, and exhibits a dose-dependent increase in size with decreasing levels of circulating thyroid hormone. Importantly, this structural abnormality is evident at modest levels of maternal thyroid hormone insufficiency, persists in adult offspring despite a return to normal hormonal status, and is dramatically reduced in size with prenatal thyroid hormone replacement. The presence of a heterotopia in these animals confirms the significant role prenatal thyroid hormone plays in normal brain development and suggests that thyroid hormone insufficiencies may contribute to the induction of some forms of cortical dysplasia.

	Materials and Methods

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Subjects
Pregnant Long-Evans rats were obtained from Charles River (Raleigh, NC) on gestational day (GD) 2 and housed individually in standard plastic hanging cages in an Association Assessment and Accreditation of Laboratory Animal Care-approved animal facility. All animal treatments were in strict accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. All efforts were made to minimize the number of animals and their suffering. Animal rooms were maintained on a 12-h light, 12-h dark schedule, and animals were permitted free access to food (rat chow; Purina, St. Louis, MO) and tap water.

Developmental hormone insufficiency
Beginning on GD 6 and continuing until postnatal day (PN) 30, dams were rendered hypothyroid by addition of 0, 1, 2, 3, or 10 ppm of the thyroid hormone synthesis inhibitor propylthiouracil (PTU) or methimazole (200 ppm) to the drinking water. The day of birth was designated PN0 and all litters were culled to 10 pups on PN3–4, retaining the maximal number of males per litter. On PN30, the offspring were weaned, transferred to plastic hanging cages (two to four per cage) and were permitted free access to food and tap water. These conditions produced graded levels of thyroid hormone reduction in dams and pups with full recovery of serum hormones to control levels at the time the adults were killed. A subset of animals (one per litter) were killed on PN23 and processed for Nissl or immunohistochemical assessment. Additional groups of animals were similarly processed on PN86.

Hormone measurements
Serum thyroid hormone measurements were evaluated according to previously published methods (15, 16). Briefly, animals were decapitated and trunk blood was sampled and allowed to clot. Serum was separated via centrifugation and stored at –80 C for later analyses. Serum concentrations of total T₄, total T₃, and TSH were analyzed by RIA (Diagnostic Products Corp., Los Angeles, CA). All samples for total T₄ and total T₃ were run in duplicate. The lowest calibrator used for hormone analysis was 10 ng/dl and 5 ng/ml for the T₃ and T₄ assays, respectively. Portions of thyroid hormone data for animals in this study were previously reported (15, 16) and are summarized in Table 1.

Thyroid hormone replacement was accomplished by insertion of osmotic Alzet minipumps (Durect Corp., Cupertino, CA) containing T₄ (4 µg/100 g body weight/d) delivered at a constant rate over 14 d. Pumps were implanted under metafane anesthesia on GD5 under the skin at the nape of the neck. Dams with pumps containing T₄ or physiologic saline were exposed to 0 or 10 ppm PTU in the drinking water beginning on GD6 and continuing until weaning. Pups from each litter were killed on PN23 and prepared for histological analysis. To determine the effectiveness of prenatal hormone supplementation, a subset of pups from each litter was killed on PN1. T₄ was reduced as a function of PTU treatment (all values fell below the level of detection of the assay, n = 5). Pups from dams exposed to PTU but supplemented with T₄ had serum T₄ levels (mean = 8.9 ± 1.7 ng/ml, n = 5) comparable with those of saline-treated controls (mean = 6.6 ± 1.6 ng/ml, n = 10).

Brain sectioning and immunohistochemistry
Animals were killed with an overdose of phenobarbital (100 mg/kg, ip) and perfusion fixed through the aorta with 4% paraformaldehyde. The brains were removed and sectioned throughout the hippocampus at 50 µm using a vibratome. Slide-mounted sections were Nissl stained, and the size of the heterotopia was estimated by multiplying the number sections in which the heterotopia was present by the section thickness of 50 µm. Free-floating sections were processed for immunohistochemistry using the methods of Goodman and Sloviter (17). Briefly, the sections were washed in 0.1 M Tris buffer (pH 7.6) followed by incubation in 1% hydrogen peroxide to remove endogenous peroxidase activity. Sections were then washed sequentially in Tris followed by Tris A (0.1 M Tris plus 0.1% Triton X-100), Tris B (0.1 M Tris, 0.1% Triton X-100, 0.05% BSA), and then incubated in one of the following antisera: monoclonal NeuN (1:5,000; Chemicon, Temecula, CA), glial fibrillary acidic protein (GFAP) (1:1,000; Chemicon), glutamic acid decarboxylase 67 (GAD-67; 1:7,000; Chemicon), calbindin (1:100,000; Sigma, St. Louis, MO), parvalbumin (1:100,000; Sigma), bromodeoxyuridine (BrdU; 1:1,000; Roche, Indianapolis, IN) or polyclonal neuropeptide Y (NPY; 1:30,000; Peninsula, San Carlos, CA) for 48 h at 4 C. On the second day of processing the sections were incubated in biotinylated secondary antiserum (horse antimouse, dilution 1:400, or goat antirabbit, dilution 1:1000; Vector Labs, Burlingame, CA) followed by avidin-biotin complex (ABC Elite, 1:1000 dilution; Vector) and visualized with diaminobenzidine as the chromogen. Stained sections were mounted on glass slides, dehydrated, and coverslipped.

	Results

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Developmental hypothyroidism induces the formation of a heterotopia
Nissl stained sections of the hippocampus and neocortex from PN23 rats developmentally exposed to PTU revealed an aberrant cluster of cells, a heterotopia, within the white matter of the corpus callosum (compare Fig. 1A with B.). This malformation, observed as early as PN3, was present in both hemispheres, was typically symmetrical and appeared at approximately the same rostral-caudal region of the brain in all animals. A heterotopia was observed in PN23 offspring of 2 ppm (six of six), 3 ppm (12 of 13), and 10 ppm (15 of 15) PTU-treated animals but was never observed in controls (none of 21) or 1 ppm (none of six) treated animals.

View larger version (66K): [in this window] [in a new window]   FIG. 1. Developmental hypothyroidism induces a bilateral malformation, a heterotopia, in the corpus callosum of the rat. A, Nissl-stained section from a control animal. B, Nissl-stained section in the same general region as the control in A from a PN23 rat exposed to 10 ppm PTU from GD6. The heterotopia appeared in both hemispheres at approximately the same rostral caudal position in the brain. Note bilateral symmetrical location of an aberrant cellular capsule in the corpus callosum. It proved difficult to match the exact rostral-caudal region in control and high-dose PTU animals due to the smaller and relatively immature brain size of the latter. C, Example of a heterotopia in a Nissl-stained section from a PN23 rat exposed to 3 ppm PTU, which reduced maternal serum T4 by approximately 45% but did not alter T3. D, A heterotopia in a Nissl-stained section from a PN86 rat exposed to 10 ppm PTU through gestation and lactation demonstrates the persistence of the brain malformation despite return to control hormone levels. E, NeuN, a neuronal nuclear marker, labels the cells within the heterotopia as neurons. F, Lack of GFAP staining, a marker of astrocytes, indicates the cells within the heterotopia are not predominantly glial cells. G, The heterotopia is present in a Nissl-stained section from PN23 rat with exposure to PTU limited to the prenatal period. H, The heterotopia was not present in a Nissl-stained section from a PN23 rat with exposure to PTU beginning on PN1. *, Above the heterotopia. CTX, Cortex; H, hippocampus; CC, corpus callosum. Calibration bar, A and B, 500 µm; C, D, G, and H, 80 µm; E and F, 50 µm.

The presence of the heterotopia in animals exposed to 2 or 3 ppm PTU (Fig. 1C) is significant because maternal T₄ was reduced by approximately 45% without altering T₃ (Table 1). The malformation remained in adult animals (PN86–200) whose exposure to PTU was terminated on PN30 (Fig. 1D), indicating persistence, even though the animals had returned to a euthyroid state. Immunohistochemical staining for NeuN, a nuclear marker of neurons (Fig. 1E), and for GFAP, a marker of astrocytes (Fig. 1F), revealed the cells within the heterotopia to be predominantly neurons.

Prenatal hypothyroidism is sufficient and necessary for formation of the heterotopia
To determine the developmental window when hormone insufficiency was critical for the formation of the heterotopia, a cross-fostering study was performed. This procedure resulted in four groups of neonates that were hormone deficient throughout the pre- and postnatal period, only prenatally, only postnatally, or not at all. Prenatal exposure was both necessary and sufficient to produce the heterotopia (compare Fig. 1G with H).

The birth date of cells within the heterotopia was determined by dosing PTU-exposed dams (10 ppm) with BrdU (50 mg/kg ip) once daily between GD14–16 or GD17–19. Individual pups from other 10 ppm litters were administered BrdU or saline once daily on PN1-PN3. On PN23, no BrdU-positive cells were detected in the heterotopia of offspring of dams injected with BrdU on GD14–16 (Fig. 2A) or receiving BrdU postnatally (data not shown). BrdU-positive cells were present in the heterotopia of rats exposed to BrdU on GD17–19 (Fig. 2B). Thus, cells within the heterotopia were born relatively late in gestation, coinciding with birth date of cells destined for the subiculum, hippocampus, and neocortical layers IV-II (18). These findings are also consistent with the requirement of a prenatal hormone deficiency for formation of the heterotopia. Differential staining with antisera against GAD-67 (Fig. 2C), NPY (Fig. 2D), parvalbumin (Fig. 2E), and calbindin (Fig. 2F) identified different subpopulations of inhibitory neurons within the heterotopia; however, the majority of neurons within the heterotopia did not express these inhibitory markers.

View larger version (56K): [in this window] [in a new window]   FIG. 2. Cells within the heterotopia are born late in gestation. A, Administration of BrdU to dams between GD14 and GD16 did not label cells within the heterotopia. B, Many cells were labeled with BrdU in the offspring of dams treated with BrdU between GD17 and GD19. Cells within the heterotopia expressed markers of inhibitory neurons: GAD-67 (C), NPY (D), parvalbumin (E), and calbindin (F). G, The heterotopia was also present in a Nissl-stained section from a PN23 rat developmentally exposed to methimazole. H, The size of the heterotopia was greatly reduced in size in animals exposed to prenatal PTU (10 ppm) plus T4 replacement. Calibration bar, A–F, 62.5 µm; G, 50 µm; H, 80 µm.

	Discussion

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The principal finding of this study was that a modest decrease in maternal T₄ during gestation can result in abnormal cortical development, which confirms the profound dependence of normal brain development on adequate levels of T₄ during gestation. Earlier studies that examined the relationship between thyroid hormone insufficiency and brain development focused on the effects of severe hormone deprivation during the early postnatal period (7, 19). The significance of this study is that changes in cortical development were observed in animals in which the degree of maternal hormone insufficiency was modest and the duration limited to the prenatal period. Modest deficiencies in maternal thyroid hormonal status can alter gene expression in the fetal brain (3), and recent reports revealed disruptions in the layering of cells in the neocortex and hippocampus after mild and transient reductions in maternal thyroid hormone (1, 8).

Formation of a cortical heterotopia requires the functional alteration of several genes. Genes regulated by thyroid hormone encode proteins essential for specific developmental events including cell proliferation, migration, myelination, synaptogenesis, and apoptosis (7, 9, 10, 11, 12, 13, 14). The observation by Martinez-Galan et al. (14) that development of radial glial cells is altered by gestational hypothyroidism is particularly relevant because radial glial migration is the primary mechanism whereby excitatory pyramidal neurons migrate to the appropriate cortical layer. However, the presence of inhibitory neurons within the heterotopia indicates that tangential migration from the medial ganglionic eminence was also impacted by prenatal thyroid hormone insufficiency (20, 21). Whereas thyroid hormone receptors have been identified on nestin-positive progenitor cells of the subventricular zone (22), it is not known whether the cells within the heterotopia express thyroid hormone receptors.

Functionally, neuronal heterotopias in humans represent an important class of malformation often associated with intractable epilepsy of childhood (23). Auso et al. (1) recently reported an increased susceptibility to audiogenic seizures in animals experiencing brief and transient reductions in thyroid hormone in the prenatal period. In animals similarly treated as those reported in this study, we also observed increases in susceptibility to pentylentetrazol-induced seizures, reductions in hippocampal inhibition (24), and perturbations in synaptic transmission, long-term potentiation, and spatial learning (16). However, the relationship of these impairments to the presence of a heterotopia has yet to be established.

These results demonstrate that subtle transient prenatal reductions of T₄ reliably produce dramatic structural alterations in the brain. The dose-dependent characteristics of these alterations are consistent with a concern that subclinical hypothyroid conditions, estimated to occur in up to 5% of women of child-bearing age (25), may result in persistent alterations in the brain of their offspring. The present findings provide an animal model of altered brain development suitable to investigate the neural substrates of cognitive deficits observed in children of undiagnosed hypothyroid women (4). Furthermore, these findings also provide a means to examine mechanisms of cortical development and cortical dysplasia that may be superior to existing models based on physiological relevance and consistency and reliability of induction. In contrast to models that rely on antimitotic agents (26) or irradiation (27), simple transient reduction of an endogenous substance during a brief prenatal window is sufficient to reliably produce consistent alterations in brain development that are not associated with toxicity to the dam or neonate.

	Footnotes

 
Disclosure Statement: The authors have nothing to declare.

First Published Online February 22, 2007

Abbreviations: BrdU, Bromodeoxyuridine; GAD-67, glutamic acid decarboxylase 67; GD, gestational day; GFAP, glial fibrillary acidic protein; NPY, neuropeptide Y; PN, postnatal day; PTU, propylthiouracil.

Received September 18, 2006.

Accepted for publication February 14, 2007.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Goodman, J. H. Articles by Gilbert, M. E. Search for Related Content PubMed PubMed Citation Articles by Goodman, J. H. Articles by Gilbert, M. E.