Role of Late Maternal Thyroid Hormones in Cerebral Cortex Development: An Experimental Model for Human Prematurity

Hypothyroxinemia affects 35–50% of neonates born prematurely (12% of births) and increases their risk of suffering neurodevelopmental alterations. We have developed an animal model to study the role of maternal thyroid hormones (THs) at the end of gestation on offspring's cerebral maturation. Pregnant rats were surgically thyroidectomized at embryonic day (E) 16 and infused with calcitonin and parathormone (late maternal hypothyroidism [LMH] rats). After birth, pups were nursed by normal rats. Pups born to LMH dams, thyroxine treated from E17 to postnatal day (P) 0, were also studied. In developing LMH pups, the cortical lamination was abnormal. At P40, heterotopic neurons were found in the subcortical white matter and in the hippocampal stratum oriens and alveus. The Zn-positive area of the stratum oriens of hippocampal CA3 was decreased by 41.5% showing altered mossy fibers’ organization. LMH pups showed delayed learning in parallel to decreased phosphorylated cAMP response element-binding protein (pCREB) and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) expression in the hippocampus. Thyroxine treatment of LMH dams reverted abnormalities. In conclusion, maternal THs are still essential for normal offspring's neurodevelopment even after onset of fetal thyroid function. Our data suggest that thyroxine treatment of premature neonates should be attempted to compensate for the interruption of the maternal supply.

[1]  M. Marín‐Padilla,et al.  Neocortical Development , 1992, Journal of Cognitive Neuroscience.

[2]  M. Elovitz,et al.  Animal models of preterm birth , 2004, Trends in Endocrinology & Metabolism.

[3]  P. C. Murphy,et al.  Cerebral Cortex , 2017, Cerebral Cortex.

[4]  J. Bland,et al.  A longitudinal assessment of thyroid hormone concentrations in preterm infants younger than 30 weeks' gestation during the first 2 weeks of life and their relationship to outcome. , 2002, Pediatrics.

[5]  T. Visser,et al.  Iodothyronine levels in the human developing brain: major regulatory roles of iodothyronine deiodinases in different areas. , 2004, The Journal of clinical endocrinology and metabolism.

[6]  T. Gudermann,et al.  Congenital hypothyroidism caused by mutations in the thyrotropin-receptor gene. , 1997, The New England journal of medicine.

[7]  J. Kok,et al.  Hypothyroxinaemia and thyroid function after preterm birth. , 2004, Seminars in neonatology : SN.

[8]  Paul J. Harrison,et al.  Neuropathological studies of synaptic connectivity in the hippocampal formation in schizophrenia , 2001, Hippocampus.

[9]  R. Palmiter,et al.  ZnT-3, a putative transporter of zinc into synaptic vesicles. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[10]  G. Innocenti,et al.  Analysis of an Experimental Cortical Network: i) Architectonics of Visual Areas 17 and 18 After Neonatal Injections of Ibotenic Acid; Similarities with Human Microgyria , 1991, Journal of neural transplantation & plasticity.

[11]  P Shaw,et al.  Neuregulin 1 (8p12) and childhood-onset schizophrenia: susceptibility haplotypes for diagnosis and brain developmental trajectories , 2007, Molecular Psychiatry.

[12]  D. Glinoer,et al.  The potential repercussions of maternal, fetal, and neonatal hypothyroxinemia on the progeny. , 2000, Thyroid : official journal of the American Thyroid Association.

[13]  J. Rovet,et al.  The role of transient hypothyroxinemia of prematurity in development of visual abilities. , 2008, Seminars in perinatology.

[14]  W. Honer,et al.  Low birthweight in schizophrenia: prematurity or poor fetal growth? , 2001, Schizophrenia Research.

[15]  P. Berbel,et al.  The changing role of maternal thyroid hormone in fetal brain development. , 2008, Seminars in perinatology.

[16]  Martin Telefont,et al.  Transient maternal hypothyroxinemia at onset of corticogenesis alters tangential migration of medial ganglionic eminence‐derived neurons , 2005, The European journal of neuroscience.

[17]  M. Saysell,et al.  MR features of developing periventricular white matter in preterm infants: evidence of glial cell migration. , 1998, AJNR. American journal of neuroradiology.

[18]  G. Innocenti,et al.  Organization of Auditory Callosal Connections in Hypothyroid Adult Rats , 1993, The European journal of neuroscience.

[19]  M. Obregon,et al.  Effects of maternal hypothyroidism on the weight and thyroid hormone content of rat embryonic tissues, before and after onset of fetal thyroid function. , 1985, Endocrinology.

[20]  J. Kok,et al.  Trials with thyroid hormone in preterm infants: clinical and neurodevelopmental effects. , 2008, Seminars in perinatology.

[21]  Y. Burns,et al.  Extremely low birth weight and control infants at 2 years corrected age: a comparison of intellectual abilities, motor performance, growth and health. , 1995, Early human development.

[22]  R. Lauro,et al.  Pax8 has a key role in thyroid cell differentiation. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[23]  D. Fisher.  The Hypothroxinemia of Prematurity , 1997 .

[24]  F. Valverde,et al.  Persistence of early-generated neurons in the rodent subplate: assessment of cell death in neocortex during the early postnatal period , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[25]  T. Clemens,et al.  Evidence that calcitonin stimulates 1,25-dihydroxyvitamin D production and intestinal absorption of calcium in vivo. , 1986, The Journal of clinical investigation.

[26]  R. Tabarés-Seisdedos,et al.  Postnatal alterations of the inhibitory synaptic responses recorded from cortical pyramidal neurons in the Lis1/sLis1 mutant mouse , 2007, Molecular and Cellular Neuroscience.

[27]  V. Ramirez-Amaya,et al.  Spatial Long-Term Memory Is Related to Mossy Fiber Synaptogenesis , 2001, The Journal of Neuroscience.

[28]  A. V. van Baar,et al.  Free thyroxine levels during the first weeks of life and neurodevelopmental outcome until the age of 5 years in very preterm infants. , 2002, Pediatrics.

[29]  J. Kratzsch,et al.  Thyroid gland development and defects. , 2008, Best practice & research. Clinical endocrinology & metabolism.

[30]  P. Berbel,et al.  A moderate and transient deficiency of maternal thyroid function at the beginning of fetal neocorticogenesis alters neuronal migration. , 2004, Endocrinology.

[31]  W. Farrugia,et al.  PTH/PTHrP receptor and mid-molecule PTHrP regulation of intrauterine PTHrP: PTH/PTHrP receptor antagonism increases SHR fetal weight. , 2004, Placenta.

[32]  T Takahashi,et al.  BUdR as an S-phase marker for quantitative studies of cytokinetic behaviour in the murine cerebral ventricular zone , 1992, Journal of neurocytology.

[33]  R. Post,et al.  Reduction of dopamine-related transcription factors Nurr1 and NGFI-B in the prefrontal cortex in schizophrenia and bipolar disorders , 2006, Schizophrenia Research.

[34]  Chung-Bin Huang,et al.  Transient Hypothyroxinemia of Prematurity is Associated with Abnormal Cranial Ultrasound and Illness Severity , 2002, American journal of perinatology.

[35]  F. Gaarskjaer.  Organization of the mossy fiber system of the rat studied in extended hippocampi. II. Experimental analysis of fiber distribution with silver impregnation methods , 1978, The Journal of comparative neurology.

[36]  M. Stoltenberg,et al.  Immersion Autometallography: Histochemical In Situ Capturing of Zinc Ions in Catalytic Zinc-Sulfur Nanocrystals , 2004, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[37]  S. Ares,et al.  Neonatal hypothyroxinemia: effects of iodine intake and premature birth. , 1997, The Journal of clinical endocrinology and metabolism.

[38]  Paul J. Harrison,et al.  Interstitial white matter neurons express less reelin and are abnormally distributed in schizophrenia: towards an integration of molecular and morphologic aspects of the neurodevelopmental hypothesis , 2003, Molecular Psychiatry.

[39]  S. Martinez,et al.  Early specification of oligodendrocytes in the chick embryonic brain. , 1999, Developmental biology.

[40]  J. Pinto-Martin,et al.  The relation of transient hypothyroxinemia in preterm infants to neurologic development at two years of age. , 1996, The New England journal of medicine.

[41]  J. Bernal,et al.  Iodine supplementation during pregnancy: a public health challenge , 2007, Trends in Endocrinology & Metabolism.

[42]  Paul J. Harrison,et al.  Cellular basis of reduced cortical reelin expression in schizophrenia. , 2006, The American journal of psychiatry.

[43]  D. Savage,et al.  Perinatal hypothyroidism decreases hippocampal mossy fiber zinc density in rats. , 1992, Neuroendocrinology.

[44]  R. Brand,et al.  The Relation between Neonatal Thyroxine Levels and Neurodevelopmental Outcome at Age 5 and 9 Years in a National Cohort of Very Preterm and/or Very Low Birth Weight Infants , 1996, Pediatric Research.

[45]  O. Paulsen,et al.  Novel markers reveal subpopulations of subplate neurons in the murine cerebral cortex. , 2009, Cerebral cortex.

[46]  P. Berbel,et al.  Role of thyroid hormones in the maturation and organisation of rat barrel cortex , 2001, Neuroscience.

[47]  S. Ares,et al.  The hypothyroxinemia of prematurity. , 1998, The Journal of clinical endocrinology and metabolism.

[48]  A. Dale,et al.  Clinical findings and white matter abnormalities seen on diffusion tensor imaging in adolescents with very low birth weight. , 2007, Brain : a journal of neurology.

[49]  Paul J. Harrison.  Schizophrenia: a disorder of neurodevelopment? , 1997, Current Opinion in Neurobiology.

[50]  C. Bramham.  Control of synaptic consolidation in the dentate gyrus: mechanisms, functions, and therapeutic implications. , 2007, Progress in brain research.

[51]  J. Samarut,et al.  Thyroid hormone receptors: lessons from knockout and knock-in mutant mice , 2003, Trends in Endocrinology & Metabolism.

[52]  Paul M. Thompson,et al.  Dynamic mapping of hippocampal development in childhood onset schizophrenia , 2007, Schizophrenia Research.

[53]  Carla J. Shatz,et al.  Subplate Neurons Regulate Maturation of Cortical Inhibition and Outcome of Ocular Dominance Plasticity , 2006, Neuron.

[54]  R. Zoeller,et al.  Timing of Thyroid Hormone Action in the Developing Brain: Clinical Observations and Experimental Findings , 2004, Journal of neuroendocrinology.

[55]  N. Uranova,et al.  Ultrastructural alterations in hippocampal mossy fiber synapses in schizophrenia: A postmortem morphometric study , 2005, Synapse.

[56]  F. Gaarskjaer.  Organization of the mossy fiber system of the rat studied in extended hippocampi. I. Terminal area related to number of granule and pyramidal cells , 1978, The Journal of comparative neurology.

[57]  M. Gilbert,et al.  Modest thyroid hormone insufficiency during development induces a cellular malformation in the corpus callosum: a model of cortical dysplasia. , 2007, Endocrinology.

[58]  R Clay Reid,et al.  Materials and Methods Som Text Figs. S1 to S7 References Movies S1 to S7 Role of Subplate Neurons in Functional Maturation of Visual Cortical Columns , 2022 .

[59]  P. Berbel,et al.  Early maternal hypothyroxinemia alters histogenesis and cerebral cortex cytoarchitecture of the progeny. , 2003, The Journal of clinical investigation.

[60]  M. Paula-Barbosa,et al.  Reorganization of mossy fiber synapses in male and female hypothyroid rats: A stereological study , 1993, The Journal of comparative neurology.

[61]  P. Gaspar,et al.  Protracted expression of serotonin transporter and altered thalamocortical projections in the barrelfield of hypothyroid rats , 2001, The European journal of neuroscience.

[62]  F. Pancetti,et al.  Maternal hypothyroxinemia impairs spatial learning and synaptic nature and function in the offspring. , 2008, Endocrinology.

[63]  Fiona L. R. Williams,et al.  Transient hypothyroxinemia in preterm infants: the role of cord sera thyroid hormone levels adjusted for prenatal and intrapartum factors. , 2005, The Journal of clinical endocrinology and metabolism.

[64]  M. Giovannini,et al.  Inhibition of acetylcholine-induced activation of extracellular regulated protein kinase prevents the encoding of an inhibitory avoidance response in the rat , 2005, Neuroscience.

[65]  B. Dani,et al.  Skeletal effects of parathyroid hormone (1–34) in ovariectomized rats with or without concurrent administration of salmon calcitonin , 2008, AAPS PharmSci.

[66]  N. Marlow,et al.  Pervasive Behavior Problems at 6 Years of Age in a Total-Population Sample of Children Born at ≤25 Weeks of Gestation , 2008, Pediatrics.

[67]  Paul J. Harrison,et al.  Neuregulin 1 and Schizophrenia: Genetics, Gene Expression, and Neurobiology , 2006, Biological Psychiatry.

[68]  Fiona L. R. Williams,et al.  Perinatal factors affecting thyroid hormone status in extreme preterm infants. , 2008, Seminars in perinatology.

[69]  R. Robertson,et al.  Do subplate neurons comprise a transient population of cells in developing neocortex of rats? , 2000, The Journal of comparative neurology.

[70]  M. Isohanni,et al.  Schizophrenia as a long-term outcome of pregnancy, delivery, and perinatal complications: a 28-year follow-up of the 1966 north Finland general population birth cohort. , 1998, The American journal of psychiatry.

[71]  E. Asztalos,et al.  Impact of neonatal thyroid hormone insufficiency and medical morbidity on infant neurodevelopment and attention following preterm birth. , 2009, Thyroid : official journal of the American Thyroid Association.