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Developmental Iodine Deficiency and Hypothyroidism Impair Neural Development, Upregulate Caveolin-1, and Downregulate Synaptotagmin-1 in the Rat Cerebellum

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Abstract

Adequate thyroid hormone is critical for cerebellar development. Developmental hypothyroidism induced by iodine deficiency during gestation and postnatal period results in permanent impairments of cerebellar development with an unclear mechanism. In the present study, we implicate cerebellar caveolin-1 and synaptotagmin-1, the two important molecules involved in neuronal development, in developmental iodine deficiency, and in developmental hypothyroidism. Two developmental rat models were created by administrating dam rats with either iodine-deficient diet or propylthiouracil (PTU, 5 or 15 ppm)-added drinking water from gestational day 6 till postnatal day (PN) 28. Nissl staining and the levels of caveolin-1 and synaptotagmin-1 in cerebella were assessed on PN28 and PN42. The results show that the numbers of Purkinje cells were reduced in the iodine-deficient and PTU-treated rats. The upregulation of caveolin-1 and the downregulation of synaptotagmin-1 were observed in both iodine-deficient and PTU-treated rats. These findings may implicate decreases in the number of Purkinje cells and the alterations in the levels of caveolin-1 and synaptotagmin-1 in the impairments of cerebellar development induced by developmental iodine deficiency and hypothyroidism.

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References

  1. Sui L, Gilbert ME (2003) Pre- and postnatal propylthiouracil-induced hypothyroidism impairs synaptic transmission and plasticity in area CA1 of the neonatal rat hippocampus. Endocrinology 144:4195–4203

    Article  PubMed  CAS  Google Scholar 

  2. Bernal J (2002) Action of thyroid hormone in brain. J Endocrinol Invest 25:268–288

    PubMed  CAS  Google Scholar 

  3. Kibirige MS, Hutchison S, Owen CJ, Delves HT (2004) Prevalence of maternal dietary iodine insufficiency in the north east of England: implications for the fetus. Arch Dis Child Fetal Neonatal Ed 89:F436–F439

    Article  PubMed  CAS  Google Scholar 

  4. Berbel P, Obregon MJ, Bernal J, Escobar del Rey F, Morreale de Escobar G (2007) Iodine supplementation during pregnancy: a public health challenge. Trends Endocrinol Metab 18:338–343

    Article  PubMed  CAS  Google Scholar 

  5. Zimmermann MB (2008) Iodine requirements and the risks and benefits of correcting iodine deficiency in populations. J Trace Elem Med Biol 22:81–92

    Article  PubMed  CAS  Google Scholar 

  6. Alissa EM, AlShali K, Ferns GA (2009) Iodine deficiency among hypothyroid patients living in Jeddah. Biol Trace Elem Res 130:193–203

    Article  PubMed  CAS  Google Scholar 

  7. Melse-Boonstra A, Jaiswal N (2010) Iodine deficiency in pregnancy, infancy and childhood and its consequences for brain development. Best Pract Res Clin Endocrinol Metab 24:29–38

    Article  PubMed  CAS  Google Scholar 

  8. Farwell AP, Dubord-Tomasetti SA (1999) Thyroid hormone regulates the expression of laminin in the developing rat cerebellum. Endocrinology 140:4221–4227

    Article  PubMed  CAS  Google Scholar 

  9. Koibuchi N, Jingu H, Iwasaki T, Chin WW (2003) Current perspectives on the role of thyroid hormone in growth and development of cerebellum. Cerebellum 2:279–289

    Article  PubMed  CAS  Google Scholar 

  10. Sinha RA, Pathak A, Kumar A, Tiwari M, Shrivastava A, Godbole MM (2009) Enhanced neuronal loss under perinatal hypothyroidism involves impaired neurotrophic signaling and increased proteolysis of p75(NTR). Mol Cell Neurosci 40:354–364

    Article  PubMed  CAS  Google Scholar 

  11. Alvarez-Dolado M, Figueroa A, Kozlov S, Sonderegger P, Furley AJ, Munoz A (2001) Thyroid hormone regulates TAG-1 expression in the developing rat brain. Eur J Neurosci 14:1209–1218

    Article  PubMed  CAS  Google Scholar 

  12. Koibuchi N (2008) The role of thyroid hormone on cerebellar development. Cerebellum 7:530–533

    Article  PubMed  CAS  Google Scholar 

  13. Gaudreault SB, Blain JF, Gratton JP, Poirier J (2005) A role for caveolin-1 in post-injury reactive neuronal plasticity. J Neurochem 92:831–839

    Article  PubMed  CAS  Google Scholar 

  14. Trushina E, Du Charme J, Parisi J, McMurray CT (2006) Neurological abnormalities in caveolin-1 knock out mice. Behav Brain Res 172:24–32

    Article  PubMed  CAS  Google Scholar 

  15. Shaul PW, Anderson RG (1998) Role of plasmalemmal caveolae in signal transduction. Am J Physiol 275:L843–L851

    PubMed  CAS  Google Scholar 

  16. Rothberg KG, Heuser JE, Donzell WC, Ying YS, Glenney JR, Anderson RG (1992) Caveolin, a protein component of caveolae membrane coats. Cell 68:673–682

    Article  PubMed  CAS  Google Scholar 

  17. Wary KK, Mariotti A, Zurzolo C, Giancotti FG (1998) A requirement for caveolin-1 and associated kinase Fyn in integrin signaling and anchorage-dependent cell growth. Cell 94:625–634

    Article  PubMed  CAS  Google Scholar 

  18. Smart EJ, Ying Y, Donzell WC, Anderson RG (1996) A role for caveolin in transport of cholesterol from endoplasmic reticulum to plasma membrane. J Biol Chem 271:29427–29435

    Article  PubMed  CAS  Google Scholar 

  19. Grande-Garcia A, del Pozo MA (2008) Caveolin-1 in cell polarization and directional migration. Eur J Cell Biol 87:641–647

    Article  PubMed  CAS  Google Scholar 

  20. Bu J, Bruckner SR, Sengoku T, Geddes JW, Estus S (2003) Glutamate regulates caveolin expression in rat hippocampal neurons. J Neurosci Res 72:185–190

    Article  PubMed  CAS  Google Scholar 

  21. Francesconi A, Kumari R, Zukin RS (2009) Regulation of group I metabotropic glutamate receptor trafficking and signaling by the caveolar/lipid raft pathway. J Neurosci 29:3590–3602

    Article  PubMed  CAS  Google Scholar 

  22. Matthew WD, Tsavaler L, Reichardt LF (1981) Identification of a synaptic vesicle-specific membrane protein with a wide distribution in neuronal and neurosecretory tissue. J Cell Biol 91:257–269

    Article  PubMed  CAS  Google Scholar 

  23. Fukuda M (2006) Distinct developmental expression of synaptotagmin I and IX in the mouse brain. Neuroreport 17:179–182

    Article  PubMed  CAS  Google Scholar 

  24. Loewen CA, Mackler JM, Reist NE (2001) Drosophila synaptotagmin I null mutants survive to early adulthood. Genesis 31:30–36

    Article  PubMed  CAS  Google Scholar 

  25. Mikoshiba K, Fukuda M, Ibata K, Kabayama H, Mizutani A (1999) Role of synaptotagmin, a Ca2+ and inositol polyphosphate binding protein, in neurotransmitter release and neurite outgrowth. Chem Phys Lipids 98:59–67

    Article  PubMed  CAS  Google Scholar 

  26. Xiao Z, Gong Y, Wang XF, Xiao F, Xi ZQ, Lu Y, Sun HB (2009) Altered expression of synaptotagmin I in temporal lobe tissue of patients with refractory epilepsy. J Mol Neurosci 38:193–200

    Article  PubMed  CAS  Google Scholar 

  27. National Research Council, Institute of Laboratory Animal Resources, Commission on Life Sciences (1996) Guide for the care and use of laboratory animals, 7th edn. National Academy Press, Washington, D.C

    Google Scholar 

  28. Dong J, Yin H, Liu W, Wang P, Jiang Y, Chen J (2005) Congenital iodine deficiency and hypothyroidism impair LTP and decrease C-fos and C-jun expression in rat hippocampus. Neurotoxicology 26:417–426

    Article  PubMed  CAS  Google Scholar 

  29. Matchett GA, Calinisan JB, Matchett GC, Martin RD, Zhang JH (2007) The effect of granulocyte-colony stimulating factor in global cerebral ischemia in rats. Brain Res 1136:200–207

    Article  PubMed  CAS  Google Scholar 

  30. He J, Yamada K, Zou LB, Nabeshima T (2001) Spatial memory deficit and neurodegeneration induced by the direct injection of okadaic acid into the hippocampus in rats. J Neural Transm 108:1435–1443

    Article  PubMed  CAS  Google Scholar 

  31. Gong J, Dong J, Wang Y, Xu H, Wei W, Zhong J, Liu W, Xi Q, Chen J (2010) Developmental iodine deficiency and hypothyroidism impair neural development, up-regulate caveolin-1, and down-regulate synaptophysin in rat hippocampus. J Neuroendocrinol 22:129–139

    Article  PubMed  CAS  Google Scholar 

  32. Gong J, Liu W, Dong J, Wang Y, Xu H, Wei W, Zhong J, Xi Q, Chen J (2010) Developmental iodine deficiency and hypothyroidism impair neural development in rat hippocampus: involvement of doublecortin and NCAM-180. BMC Neurosci 11:50

    Article  PubMed  Google Scholar 

  33. Tang Z, Liu W, Yin H, Wang P, Dong J, Wang Y, Chen J (2007) Investigation of intelligence quotient and psychomotor development in schoolchildren in areas with different degrees of iodine deficiency. Asia Pac J Clin Nutr 16:731–737

    PubMed  Google Scholar 

  34. Benton D (2008) Micronutrient status, cognition and behavioral problems in childhood. Eur J Nutr 3:38–50

    Article  Google Scholar 

  35. Zhang L, Sun YN, Li YM, Lin LX, Ye Y, Yan YQ, Chen ZP (2011) Effect of different iodine nutrition on cerebellum Pcp-2 in rat offspring during lactation. Biol Trace Elem Res. doi:10.1007/s12011-011-8991-3

    Google Scholar 

  36. Koibuchi N (2009) Animal models to study thyroid hormone action in cerebellum. Cerebellum 8:89–97

    Article  PubMed  CAS  Google Scholar 

  37. Dong H, Yauk CL, Rowan-Carroll A, You SH, Zoeller RT, Lambert I, Wade MG (2009) Identification of thyroid hormone receptor binding sites and target genes using ChIP-on-chip in developing mouse cerebellum. PLoS ONE 4:e4610

    Article  PubMed  Google Scholar 

  38. Vallortigara J, Alfos S, Micheau J, Higueret P, Enderlin V (2008) T3 administration in adult hypothyroid mice modulates expression of proteins involved in striatal synaptic plasticity and improves motor behavior. Neurobiol Dis 31:378–385

    Article  PubMed  CAS  Google Scholar 

  39. Moriyama K, Tagami T, Usui T, Naruse M, Nambu T, Hataya Y, Kanamoto N, Li YS, Yasoda A, Arai H, Nakao K (2007) Antithyroid drugs inhibit thyroid hormone receptor-mediated transcription. J Clin Endocrinol Metab 92:1066–1072

    Article  PubMed  CAS  Google Scholar 

  40. Shrader RE, Keen CL, Hurley LS, Zeman FJ (1982) Hematologic and trace element alterations following chronic maternal ingestion of propylthiourea. Exp Hematol 10:44–55

    PubMed  CAS  Google Scholar 

  41. Gonzalez-Reimers E, Santolaria-Fernandez F, Perez-Labajos J, Rodriguez-Moreno F, Martinez-Riera A, Hernandez-Torres O, Valladares-Parrilla F, Molina-Perez M (1996) Relative and combined effects of propylthiouracil, ethanol and protein deficiency on liver histology and hepatic iron, zinc, manganese and copper contents. Alcohol 31:535–545

    Article  CAS  Google Scholar 

  42. Kazi TG, Kandhro GA, Afridi HI, Kazi N, Baig JA, Arain MB, Shah AQ, Syed N, Kumar S, Kolachi NF, Khan S (2010) Interaction of copper with iron, iodine, and thyroid hormone status in goitrous patients. Biol Trace Elem Res 134:265–279

    Article  PubMed  CAS  Google Scholar 

  43. Koibuchi N, Chin WW (1999) Mechanisms underlying neurological abnormalities resulting from developmental hypothyroidism. Curr Opin Endocrinol Diabetes Obes 6:26–32

    Article  Google Scholar 

  44. Howdeshell KL (2002) A model of the development of the brain as a construct of the thyroid system. Environ Health Perspect 110:337–348

    Article  PubMed  CAS  Google Scholar 

  45. Virgintino D, Robertson D, Errede M, Benagiano V, Girolamo F, Maiorano E, Roncali L, Bertossi M (2002) Expression of caveolin-1 in human brain microvessels. Neuroscience 115:145–152

    Article  PubMed  CAS  Google Scholar 

  46. Poirier J (1994) Apolipoprotein E in animal models of CNS injury and in Alzheimer’s disease. Trends Neurosci 17:525–530

    Article  PubMed  CAS  Google Scholar 

  47. Royland JE, Parker JS, Gilbert ME (2008) A genomic analysis of subclinical hypothyroidism in hippocampus and neocortex of the developing rat brain. J Neuroendocrinol 20:1319–1338

    Article  PubMed  CAS  Google Scholar 

  48. Head BP, Peart JN, Panneerselvam M, Yokoyama T, Pearn ML, Niesman IR, Bonds JA, Schilling JM, Miyanohara A, Headrick J, Ali SS, Roth DM, Patel PM, Patel HH (2010) Loss of caveolin-1 accelerates neurodegeneration and aging. PLoS ONE 5:e15697

    Article  PubMed  CAS  Google Scholar 

  49. Littleton JT, Serano TL, Rubin GM, Ganetzky B, Chapman ER (1999) Synaptic function modulated by changes in the ratio of synaptotagmin I and IV. Nature 400:757–760

    Article  PubMed  CAS  Google Scholar 

  50. Zhu DF, Liu CL, Xu YX, Zhan Y, Hu HL, Jia XM, Chen GH (2011) Effect of thyroxine on synaptotagmin 1 and SNAP-25 expression in dorsal hippocampus of adult-onset hypothyroid rats. J Endocrinol Invest 34(4):280–286. doi:10.3275/7106

    PubMed  Google Scholar 

  51. Xi D, Chin H, Gainer H (1999) Analysis of synaptotagmin I–IV messenger RNA expression and developmental regulation in the rat hypothalamus and pituitary. Neuroscience 88:425–435

    Article  PubMed  CAS  Google Scholar 

  52. Lakshmy R, Srinivasarao P (1997) Effect of thiocyanate on microtubule assembly in rat brain during postnatal development. Int J Dev Neurosci 15:87–94

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the National Natural Science Foundation of China [grant number 30800896] and also supported by Natural Science Foundation of Liaoning Province, China for Ph.D. holders [grant number 20081053]. The excellent theoretical and technical help of Professor Hong Lai and Professor Zhanyou Wang from the College of Basic Medical Sciences at China Medical University is gratefully acknowledged.

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Correspondence to Jie Chen.

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Wang, Y., Zhong, J., Wei, W. et al. Developmental Iodine Deficiency and Hypothyroidism Impair Neural Development, Upregulate Caveolin-1, and Downregulate Synaptotagmin-1 in the Rat Cerebellum. Biol Trace Elem Res 144, 1039–1049 (2011). https://doi.org/10.1007/s12011-011-9089-7

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