Skip to main content
SpringerLink
Log in

Hypothyroidism and Cognitive Disorders during Development and Adulthood: Implications in the Central Nervous System

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Thyroid hormones (THs) play a critical function in fundamental signaling of the body regulating process such as metabolism of glucose and lipids, cell maturation and proliferation, and neurogenesis, to name just a few. THs trigger biological effects both by directly affecting gene expression through the interaction with nuclear receptors (genomic effects) and by activating protein kinases and/or ion channels (short-term effects). For years, a close relationship between the THs hormones and the central nervous system (CNS) has been described, not only for neuronal cells but also for glial development and differentiation. A deficit in thyroid hormones triiodothyronine (T3) and thyroxine (T4) is observed in the hypothyroid condition, generated by a iodine deficiency or an autoimmune response of the body. In the hypothyroid condition, several cellular deregulation and alterations have been described in dendrite spine morphology, cell migration and proliferation, and impaired synaptic transmission in the hippocampus, among others. The aim of this review is to describe the role of the thyroid hormones with focus in brain function and neurodegenerative disorders.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Bernal J (2000) Thyroid hormones in brain development and function. Endotext 3:1–48. https://doi.org/10.1038/ncpendmet0424

    Article  CAS  Google Scholar 

  2. Cheng SY, Leonard JL, Davis PJ (2010) Molecular aspects of thyroid hormone actions. Endocr Rev 31:139–170

    Article  CAS  Google Scholar 

  3. Angelousi A, Kassi E, Nasiri-Ansari N, Weickert MO, Randeva H, Kaltsas G (2018) Clock genes alterations and endocrine disorders. Eur J Clin Invest 48:e12927. https://doi.org/10.1111/eci.12927

    Article  CAS  PubMed  Google Scholar 

  4. Lazarus JH (2002) Epidemiology and prevention of thyroid disease in pregnancy. Thyroid 12:861–865. https://doi.org/10.1089/105072502761016485

    Article  PubMed  Google Scholar 

  5. Vanderpump MPJ (2011) The epidemiology of thyroid disease. Br Med Bull 99:39–51. https://doi.org/10.1093/bmb/ldr030

    Article  PubMed  Google Scholar 

  6. Korevaar TIM, Muetzel R, Medici M, Chaker L, Jaddoe VWV, de Rijke YB, Steegers EAP, Visser TJ et al (2016) Association of maternal thyroid function during early pregnancy with offspring IQ and brain morphology in childhood: a population-based prospective cohort study. Lancet Diabetes Endocrinol 4:35–43. https://doi.org/10.1016/S2213-8587(15)00327-7

    Article  CAS  PubMed  Google Scholar 

  7. Modesto T, Tiemeier H, Peeters RP, Jaddoe VWV, Hofman A, Verhulst FC, Ghassabian A (2015) Maternal mild thyroid hormone insufficiency in early pregnancy and attention-deficit/hyperactivity disorder symptoms in children. JAMA Pediatr 169:838–845. https://doi.org/10.1001/jamapediatrics.2015.0498

    Article  PubMed  Google Scholar 

  8. Zimmermann MB (2009) Iodine deficiency. Endocr Rev 30:376–408

    Article  CAS  Google Scholar 

  9. Koromilas C, Liapi C, Schulpis KH, Kalafatakis K, Zarros A, Tsakiris S (2010) Structural and functional alterations in the hippocampus due to hypothyroidism. Metab Brain Dis 25:339–354

    Article  CAS  Google Scholar 

  10. Yu J, Tang Y-Y, Feng H-B, Cheng X-X (2014) A behavioral and micro positron emission tomography imaging study in a rat model of hypothyroidism. Behav Brain Res 271:228–233. https://doi.org/10.1016/j.bbr.2014.06.019

    Article  PubMed  Google Scholar 

  11. Jang C, Oh SF, Wada S, Rowe GC, Liu L, Chan MC, Rhee J, Hoshino A et al (2016) A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance. Nat Med 22:421–426. https://doi.org/10.1038/nm.4057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Martínez-Sánchez N, Alvarez CV, Fernø J, Nogueiras R, Diéguez C, López M (2014) Hypothalamic effects of thyroid hormones on metabolism. Best Pract Res Clin Endocrinol Metab 28:703–712

    Article  Google Scholar 

  13. Munhoz RP, Teive HAG, Troiano AR et al (2004) Parkinson’s disease and thyroid dysfunction. Parkinsonism Relat Disord 10:381–383. https://doi.org/10.1016/j.parkreldis.2004.03.008

    Article  PubMed  Google Scholar 

  14. Chaalal A, Poirier R, Blum D, Gillet B, le Blanc P, Basquin M, Buée L, Laroche S et al (2014) PTU-induced hypothyroidism in rats leads to several early neuropathological signs of Alzheimer’s disease in the hippocampus and spatial memory impairments. Hippocampus 24:1381–1393. https://doi.org/10.1002/hipo.22319

    Article  CAS  PubMed  Google Scholar 

  15. Garcia-Moreno JM, Chacon J (2002) Hypothyroidism concealed by Parkinson’s disease. Rev Neurol 35:741–742

    CAS  PubMed  Google Scholar 

  16. Bernal J, Guadaño-Ferraz A, Morte B (2015) Thyroid hormone transporters-functions and clinical implications. Nat Rev Endocrinol 11:406–417

    Article  CAS  Google Scholar 

  17. Hammes SR, Davis PJ (2015) Overlapping nongenomic and genomic actions of thyroid hormone and steroids. Best Pract Res Clin Endocrinol Metab 29:581–593. https://doi.org/10.1016/j.beem.2015.04.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mullur R, Liu Y-Y, Brent GA (2014) Thyroid hormone regulation of metabolism. Physiol Rev 94:355–382. https://doi.org/10.1152/physrev.00030.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bowers J, Terrien J, Clerget-Froidevaux MS, Gothié JD, Rozing MP, Westendorp RGJ, van Heemst D, Demeneix BA (2013) Thyroid hormone signaling and homeostasis during aging. Endocr Rev 34:556–589

    Article  CAS  Google Scholar 

  20. Jansen J, Friesema ECH, Milici C, Visser TJ (2005) Thyroid hormone transporters in health and disease. Thyroid 15:757–768. https://doi.org/10.1089/thy.2005.15.757

    Article  CAS  PubMed  Google Scholar 

  21. Bernal J (2002) Action of thyroid hormone in brain. J Endocrinol Investig 25:268–288. https://doi.org/10.1007/BF03344003

    Article  CAS  Google Scholar 

  22. Ortiga-Carvalho TM, Sidhaye AR, Wondisford FE (2014) Thyroid hormone receptors and resistance to thyroid hormone disorders. Nat Rev Endocrinol 10:582–591

    Article  CAS  Google Scholar 

  23. Alvarez-Dolado M, Ruiz M, Del Río JA et al (1999) Thyroid hormone regulates reelin and dab1 expression during brain development. J Neurosci 19:6979–6993

    Article  CAS  Google Scholar 

  24. Sui L, Ren W-W, Li B-M (2010) Administration of thyroid hormone increases reelin and brain-derived neurotrophic factor expression in rat hippocampus in vivo. Brain Res 1313:9–24. https://doi.org/10.1016/j.brainres.2009.12.010

    Article  CAS  PubMed  Google Scholar 

  25. Pathak A, Sinha RA, Mohan V, Mitra K, Godbole MM (2011) Maternal thyroid hormone before the onset of fetal thyroid function regulates reelin and downstream signaling cascade affecting neocortical neuronal migration. Cereb Cortex 21:11–21. https://doi.org/10.1093/cercor/bhq052

    Article  PubMed  Google Scholar 

  26. Gil-Ibáñez P, Bernal J, Morte B (2014) Thyroid hormone regulation of gene expression in primary cerebrocortical cells: role of thyroid hormone receptor subtypes and interactions with retinoic acid and glucocorticoids. PLoS One 9. https://doi.org/10.1371/journal.pone.0091692

    Article  Google Scholar 

  27. Diez D, Grijota-Martinez C, Agretti P, de Marco G, Tonacchera M, Pinchera A, Morreale de Escobar G, Bernal J et al (2008) Thyroid hormone action in the adult brain: gene expression profiling of the effects of single and multiple doses of triiodo-L-thyronine in the rat striatum. Endocrinology 149:3989–4000. https://doi.org/10.1210/en.2008-0350

    Article  CAS  PubMed  Google Scholar 

  28. Potter GB, Zarach JM, Sisk JM, Thompson CC (2002) The thyroid hormone-regulated corepressor hairless associates with histone deacetylases in neonatal rat brain. Mol Endocrinol 16:2547–2560. https://doi.org/10.1210/me.2002-0115

    Article  CAS  PubMed  Google Scholar 

  29. Bonett RM, Hu F, Bagamasbad P, Denver RJ (2009) Stressor and glucocorticoid-dependent induction of the immediate early gene kruppel-like factor 9: implications for neural development and plasticity. Endocrinology 150:1757–1765. https://doi.org/10.1210/en.2008-1441

    Article  CAS  PubMed  Google Scholar 

  30. Gilbert ME, Sanchez-Huerta K, Wood C (2016) Mild thyroid hormone insufficiency during development compromises activity-dependent neuroplasticity in the hippocampus of adult male rats. Endocrinology 157:774–787. https://doi.org/10.1210/en.2015-1643

    Article  CAS  PubMed  Google Scholar 

  31. Desouza LA, Sathanoori M, Kapoor R, Rajadhyaksha N, Gonzalez LE, Kottmann AH, Tole S, Vaidya VA (2011) Thyroid hormone regulates the expression of the sonic hedgehog signaling pathway in the embryonic and adult mammalian brain. Endocrinology 152:1989–2000. https://doi.org/10.1210/en.2010-1396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kaleka KS, Gerges NZ (2016) Neurogranin restores amyloid β-mediated synaptic transmission and long-term potentiation deficits. Exp Neurol 277:115–123. https://doi.org/10.1016/j.expneurol.2015.12.013

    Article  CAS  PubMed  Google Scholar 

  33. Farwell AP, Tranter MP, Leonard JL (1995) Thyroxine-dependent regulation of integrin-laminin interactions in astrocytes. Endocrinology 136:3909–3915. https://doi.org/10.1210/endo.136.9.7649099

    Article  CAS  PubMed  Google Scholar 

  34. Farwell AP, Dubord-Tomasetti SA (1999) Thyroid hormone regulates the expression of laminin in the developing rat cerebellum. Endocrinology 140:4221–4227. https://doi.org/10.1210/endo.140.9.7007

    Article  CAS  PubMed  Google Scholar 

  35. 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. https://doi.org/10.1111/j.1365-2826.2008.01793.x

    Article  CAS  PubMed  Google Scholar 

  36. Brent GA (2012) Mechanisms of thyroid hormone action. J Clin Invest 122:3035–3043. https://doi.org/10.1172/JCI60047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Dräger UC (2006) Retinoic acid signaling in the functioning brain. Sci STKE 2006(324):pe10

    PubMed  Google Scholar 

  38. Fuhrer D, Brix K, Biebermann H (2015) Understanding the healthy thyroid state in 2015. Eur Thyroid J 4:1–8. https://doi.org/10.1159/000431318

    Article  PubMed  PubMed Central  Google Scholar 

  39. Gereben B, McAninch EA, Ribeiro MO, Bianco AC (2015) Scope and limitations of iodothyronine deiodinases in hypothyroidism. Nat Rev Endocrinol 11:642–652

    Article  CAS  Google Scholar 

  40. Saravanan P, Chau WF, Roberts N, Vedhara K, Greenwood R, Dayan CM (2002) Psychological well-being in patients on “adequate” doses of L-thyroxine: results of a large, controlled community-based questionnaire study. Clin Endocrinol 57:577–585. https://doi.org/10.1046/j.1365-2265.2002.01654.x

    Article  CAS  Google Scholar 

  41. Blum MR, Wijsman LW, Virgini VS, Bauer DC, den Elzen WPJ, Jukema JW, Buckley BM, de Craen AJM et al (2016) Subclinical thyroid dysfunction and depressive symptoms among the elderly: a prospective cohort study. Neuroendocrinology 103:291–299. https://doi.org/10.1159/000437387

    Article  CAS  PubMed  Google Scholar 

  42. Jia Y, Zhong S, Wang Y, Liu T, Liao X, Huang L (2015) The correlation between biochemical abnormalities in frontal white matter, hippocampus and serum thyroid hormone levels in first-episode patients with major depressive disorder. J Affect Disord 180:162–169. https://doi.org/10.1016/j.jad.2015.04.005

    Article  CAS  PubMed  Google Scholar 

  43. Kratzsch J, Pulzer F (2008) Thyroid gland development and defects. Best Pract Res Clin Endocrinol Metab 22:57–75. https://doi.org/10.1016/j.beem.2007.08.006

    Article  CAS  PubMed  Google Scholar 

  44. Farahvar A, Meisami E (2007) Novel two-dimensional morphometric maps and quantitative analysis reveal marked growth and structural recovery of the rat hippocampal regions from early hypothyroid retardation. Exp Neurol 204:541–555. https://doi.org/10.1016/j.expneurol.2006.10.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Madeira MD, Cadete-Leite A, Andrade JP, Paula-Barbosa MM (1991) Effects of hypothyroidism upon the granular layer of the dentate gyrus in male and female adult rats: a morphometric study. J Comp Neurol 314:171–186. https://doi.org/10.1002/cne.903140116

    Article  CAS  PubMed  Google Scholar 

  46. Madeira MD, Sousa N, Lima-Andrade MT, Calheiros F, Cadete-Leite A, Paula-Barbosa MM (1992) Selective vulnerability of the hippocampal pyramidal neurons to hypothyroidism in male and female rats. J Comp Neurol 322:501–518. https://doi.org/10.1002/cne.903220405

    Article  CAS  PubMed  Google Scholar 

  47. Rodger J, Salvatore L, Migani P (2012) Should i stay or should i go? Ephs and ephrins in neuronal migration. NeuroSignals 20:190–201. https://doi.org/10.1159/000333784

    Article  CAS  PubMed  Google Scholar 

  48. Shiraki A, Saito F, Akane H, Takeyoshi M, Imatanaka N, Itahashi M, Yoshida T, Shibutani M (2014) Expression alterations of genes on both neuronal and glial development in rats after developmental exposure to 6-propyl-2-thiouracil. Toxicol Lett 228:225–234. https://doi.org/10.1016/j.toxlet.2014.04.018

    Article  CAS  PubMed  Google Scholar 

  49. Chen C, Zhou Z, Zhong M, Zhang Y, Li M, Zhang L, Qu M, Yang J et al (2012) Thyroid hormone promotes neuronal differentiation of embryonic neural stem cells by inhibiting STAT3 signaling through TRα1. Stem Cells Dev 21:2667–2681. https://doi.org/10.1089/scd.2012.0023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Gilbert ME, Sui L (2006) Dose-dependent reductions in spatial learning and synaptic function in the dentate gyrus of adult rats following developmental thyroid hormone insufficiency. Brain Res 1069:10–22. https://doi.org/10.1016/j.brainres.2005.10.049

    Article  CAS  PubMed  Google Scholar 

  51. Gilbert ME (2004) Alterations in synaptic transmission and plasticity in area CA1 of adult hippocampus following developmental hypothyroidism. Dev Brain Res 148:11–18. https://doi.org/10.1016/j.devbrainres.2003.09.018

    Article  CAS  Google Scholar 

  52. Sui L, Anderson WL, Gilbert ME (2005) Impairment in short-term but enhanced long-term synaptic potentiation and ERK activation in adult hippocampal area CA1 following developmental thyroid hormone insufficiency. Toxicol Sci 85:647–656. https://doi.org/10.1093/toxsci/kfi095

    Article  CAS  PubMed  Google Scholar 

  53. Amano I, Takatsuru Y, Khairinisa MA, et al (2018) Effects of mild perinatal hypothyroidism on cognitive function of adult male offspring. Endocrinology 159(4):1910–1921. https://doi.org/10.1210/en.2017-03125

    Article  Google Scholar 

  54. Kawahori K, Hashimoto K, Yuan X et al (2018) Mild maternal hypothyroxinemia during pregnancy induces persistent DNA hypermethylation in the hippocampal brain-derived neurotrophic factor gene in mouse offspring. Thyroid 28:395–406. https://doi.org/10.1089/thy.2017.0331

    Article  CAS  PubMed  Google Scholar 

  55. Salazar P, Cisternas P, Codocedo JF, Inestrosa NC (2017) Induction of hypothyroidism during early postnatal stages triggers a decrease in cognitive performance by decreasing hippocampal synaptic plasticity. Biochim Biophys Acta Mol basis Dis 1863:870–883. https://doi.org/10.1016/j.bbadis.2017.01.002

    Article  CAS  PubMed  Google Scholar 

  56. Wang C (2013) The relationship between type 2 diabetes mellitus and related thyroid diseases. J Diabetes Res 2013:390534

    PubMed  PubMed Central  Google Scholar 

  57. Iwen KA, Schröder E, Brabant G (2013) Thyroid hormones and the metabolic syndrome. Eur Thyroid J 2:83–92. https://doi.org/10.1159/000351249

    Article  PubMed  PubMed Central  Google Scholar 

  58. Wakim AN, Polizotto SL, Buffo MJ, Marrero MA, Burholt DR (1993) Thyroid hormones in human follicular fluid and thyroid hormone receptors in human granulosa cells. Fertil Steril 59:1187–1190. https://doi.org/10.1016/S0015-0282(16)55974-3

    Article  CAS  PubMed  Google Scholar 

  59. Mellert W, Deckardt K, Walter J, Gfatter S, van Ravenzwaay B (2003) Detection of endocrine-modulating effects of the antithyroid acting drug 6-propyl-2-thiouracil in rats, based on the “Enhanced OECD Test Guideline 407”. Regul Toxicol Pharmacol 38:368–377

    Article  CAS  Google Scholar 

  60. Bauer M, Silverman DHS, Schlagenhauf F, London ED, Geist CL, van Herle K, Rasgon N, Martinez D et al (2009) Brain glucose metabolism in hypothyroidism: a positron emission tomography study before and after thyroid hormone replacement therapy. J Clin Endocrinol Metab 94:2922–2929. https://doi.org/10.1210/jc.2008-2235

    Article  CAS  PubMed  Google Scholar 

  61. Burgess N, Maguire EA, O’Keefe J (2002) The human hippocampus and spatial and episodic memory. Neuron 35:625–641

    Article  CAS  Google Scholar 

  62. Davidson RJ, Lewis DA, Alloy LB, Amaral DG, Bush G, Cohen JD, Drevets WC, Farah MJ et al (2002) Neural and behavioral substrates of mood and mood regulation. Biol Psychiatry 52:478–502

    Article  Google Scholar 

  63. Miao Q, Zhang S, Guan YH, Ye HY, Zhang ZY, Zhang QY, Xue RD, Zeng MF et al (2011) Reversible changes in brain glucose metabolism following thyroid function normalization in hyperthyroidism. AJNR Am J Neuroradiol 32:1034–1042. https://doi.org/10.3174/ajnr.A2449

    Article  CAS  PubMed  Google Scholar 

  64. Khan JY, Rajakumar RA, Devaskar UP, Weissfeld LA, Devaskar SU (1999) Effect of primary congenital hypothyroidism upon expression of genes mediating murine brain glucose uptake. Pediatr Res 45:718–725

    Article  CAS  Google Scholar 

  65. Mooradian AD, Girgis W, Shah GN (1997) Thyroid hormone-induced GLUT-1 expression in rat cerebral tissue: effect of age. Brain Res 747:144–146. https://doi.org/10.1016/S0006-8993(96)01110-9

    Article  CAS  PubMed  Google Scholar 

  66. Yau S, Li A, So K-F (2015) Involvement of adult hippocampal neurogenesis in learning and forgetting. Neural Plast 2015:717958–717913. https://doi.org/10.1155/2015/717958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kapoor R, van Hogerlinden M, Wallis K, Ghosh H, Nordstrom K, Vennstrom B, Vaidya VA (2010) Unliganded thyroid hormone receptor alpha1 impairs adult hippocampal neurogenesis. FASEB J 24:4793–4805. https://doi.org/10.1096/fj.10-161802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Munoz A, Wrighton C, Seliger B et al (1993) Thyroid hormone receptor/c-erbA: Control of commitment and differentiation in the neuronal/chromaffin progenitor line PC12. J Cell Biol 121:423–438

    Article  CAS  Google Scholar 

  69. Sjögren M, Alkemade A, Mittag J, Nordström K, Katz A, Rozell B, Westerblad H, Arner A et al (2007) Hypermetabolism in mice caused by the central action of an unliganded thyroid hormone receptor α1. EMBO J 26:4535–4545. https://doi.org/10.1038/sj.emboj.7601882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Varela L, Martínez-Sánchez N, Gallego R, Vázquez MJ, Roa J, Gándara M, Schoenmakers E, Nogueiras R et al (2012) Hypothalamic mTOR pathway mediates thyroid hormone-induced hyperphagia in hyperthyroidism. J Pathol 227:209–222. https://doi.org/10.1002/path.3984

    Article  CAS  PubMed  Google Scholar 

  71. Biessels GJ, Kappelle LJ (2005) Increased risk of Alzheimer’s disease in type II diabetes: insulin resistance of the brain or insulin-induced amyloid pathology? Biochem Soc Trans 33:1041–1044

    Article  CAS  Google Scholar 

  72. Panveloski-Costa AC, Silva Teixeira S, Ribeiro IMR, Serrano-Nascimento C, das Neves RX, Favaro RR, Seelaender M, Antunes VR et al (2016) Thyroid hormone reduces inflammatory cytokines improving glycaemia control in alloxan-induced diabetic wistar rats. Acta Physiol 217:130–140. https://doi.org/10.1111/apha.12647

    Article  CAS  Google Scholar 

  73. Prieto-Almeida F, Panveloski-Costa AC, Crunfli F, da Silva Teixeira S, Nunes MT, Torrão AS (2018) Thyroid hormone improves insulin signaling and reduces the activation of neurodegenerative pathway in the hippocampus of diabetic adult male rats. Life Sci 192:253–258. https://doi.org/10.1016/j.lfs.2017.11.013

    Article  CAS  PubMed  Google Scholar 

  74. Tan ZS, Beiser A, Vasan RS et al (2008) Thyroid function and the risk of Alzheimer disease: The Framingham study. Arch Intern Med 168:1514–1520. https://doi.org/10.1001/archinte.168.14.1514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Li X, Sundquist J, Sundquist K (2012) Subsequent risks of Parkinson disease in patients with autoimmune and related disorders: a nationwide epidemiological study from Sweden. Neurodegener Dis 10:277–284. https://doi.org/10.1159/000333222

    Article  CAS  PubMed  Google Scholar 

  76. Andersen SL, Laurberg P, Wu CS, Olsen J (2014) Attention deficit hyperactivity disorder and autism spectrum disorder in children born to mothers with thyroid dysfunction: a Danish nationwide cohort study. BJOG 121:1365–1374. https://doi.org/10.1111/1471-0528.12681

    Article  CAS  PubMed  Google Scholar 

  77. Baxter AJ, Brugha TS, Erskine HE, Scheurer RW, Vos T, Scott JG (2014) The epidemiology and global burden of autism spectrum disorders. Psychol Med 45:1–13. https://doi.org/10.1017/s003329171400172x

    Article  Google Scholar 

  78. Khan A, Harney JW, Zavacki AM, Sajdel-Sulkowska EM (2014) Disrupted brain thyroid hormone homeostasis and altered thyroid hormone-dependent brain gene expression in autism spectrum disorders. J Physiol Pharmacol 65:257–272

    CAS  PubMed  Google Scholar 

  79. Sadamatsu M, Kanai H, Xu X, Liu Y, Kato N (2006) Review of animal models for autism: implication of thyroid hormone. Congenit Anom (Kyoto) 46:1–9

    Article  CAS  Google Scholar 

  80. Wu S, Ding Y, Wu F, Li R, Xie G, Hou J, Mao P (2015) Family history of autoimmune diseases is associated with an increased risk of autism in children: a systematic review and meta-analysis. Neurosci Biobehav Rev 55:322–332

    Article  Google Scholar 

  81. Roman GC, Ghassabian A, Bongers-Schokking JJ et al (2013) Association of gestational maternal hypothyroxinemia and increased autism risk. Ann Neurol 74:733–742. https://doi.org/10.1002/ana.23976

    Article  CAS  PubMed  Google Scholar 

  82. Brown AS, Surcel H-M, Hinkka-Yli-Salomäki S, Cheslack-Postava K, Bao Y, Sourander A (2015) Maternal thyroid autoantibody and elevated risk of autism in a national birth cohort. Prog Neuro-Psychopharmacol Biol Psychiatry 57:86–92. https://doi.org/10.1016/j.pnpbp.2014.10.010

    Article  CAS  Google Scholar 

  83. Molloy CA, Morrow AL, Meinzen-Derr J, Dawson G, Bernier R, Dunn M, Hyman SL, McMahon WM et al (2006) Familial autoimmune thyroid disease as a risk factor for regression in children with autism spectrum disorder: a CPEA study. J Autism Dev Disord 36:317–324. https://doi.org/10.1007/s10803-005-0071-0

    Article  PubMed  Google Scholar 

  84. Heinzel S, Roeben B, Ben-Shlomo Y, Lerche S, Alves G, Barone P, Behnke S, Berendse HW et al (2016) Prodromal markers in Parkinson’s disease: limitations in longitudinal studies and lessons learned. Front Aging Neurosci 8:147

    Article  Google Scholar 

  85. Sveinbjornsdottir S (2016) The clinical symptoms of Parkinson’s disease. J Neurochem 139(Suppl 1):318–324

    Article  CAS  Google Scholar 

  86. Berger JR, Kelley RE (1981) Thyroid function in Parkinson disease. Neurology 31:93–95. https://doi.org/10.1212/WNL.31.1.93

    Article  CAS  PubMed  Google Scholar 

  87. Fernández E, García-Moreno J-M, Martín de Pablos A, Chacón J (2014) May the thyroid gland and thyroperoxidase participate in nitrosylation of serum proteins and sporadic Parkinson’s disease? Antioxid Redox Signal 21:2143–2148. https://doi.org/10.1089/ars.2014.6072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362:329–344. https://doi.org/10.1056/NEJMra0909142

    Article  CAS  PubMed  Google Scholar 

  89. Cerpa W, Dinamarca MC, Inestrosa NC et al (2008) Structure-function implications in Alzheimer’s disease: effect of Abeta oligomers at central synapses. Curr Alzheimer Res 5:233–243. https://doi.org/10.2174/156720508784533321

    Article  CAS  PubMed  Google Scholar 

  90. Chen Z, Zhong C (2013) Decoding Alzheimer’s disease from perturbed cerebral glucose metabolism: implications for diagnostic and therapeutic strategies. Prog Neurobiol 108:21–43. https://doi.org/10.1016/j.pneurobio.2013.06.004

    Article  CAS  PubMed  Google Scholar 

  91. Qiu C, Kivipelto M, Von Strauss E (2009) Epidemiology of Alzheimer’s disease: occurrence, determinants, and strategies toward intervention. Dialogues Clin Neurosci 11:111–128

    PubMed  PubMed Central  Google Scholar 

  92. Contreras-Jurado C, Pascual A (2012) Thyroid hormone regulation of APP (β-amyloid precursor protein) gene expression in brain and brain cultured cells. Neurochem Int 60:484–487. https://doi.org/10.1016/j.neuint.2012.01.027

    Article  CAS  PubMed  Google Scholar 

  93. Ghenimi N, Alfos S, Redonnet A et al (2010) Adult-onset hypothyroidism induces the amyloidogenic pathway of amyloid precursor protein processing in the rat hippocampus. J Neuroendocrinol 22:951–959. https://doi.org/10.1111/j.1365-2826.2010.02002.x

    Article  CAS  PubMed  Google Scholar 

  94. Sampaolo S, Campos-Barros A, Mazziotti G, Carlomagno S, Sannino V, Amato G, Carella C, di Iorio G (2005) Increased cerebrospinal fluid levels of 3,3′,5′-triiodothyronine in patients with Alzheimer’s disease. J Clin Endocrinol Metab 90:198–202. https://doi.org/10.1210/jc.2004-1083

    Article  CAS  PubMed  Google Scholar 

  95. Yong-Hong L, Xiao-Dong P, Chang-Quan H et al (2013) Hypothalamic-pituitary-thyroid axis in patients with Alzheimer disease (AD). J Investig Med 61:578–581. https://doi.org/10.2310/JIM.0b013e318280aafb

    Article  CAS  PubMed  Google Scholar 

  96. Vargas JY, Ahumada J, Arrázola MS, Fuenzalida M, Inestrosa NC (2015) WASP-1, a canonical Wnt signaling potentiator, rescues hippocampal synaptic impairments induced by Aβ oligomers. Exp Neurol 264:14–25. https://doi.org/10.1016/j.expneurol.2014.11.005

    Article  CAS  PubMed  Google Scholar 

  97. Vargas JY, Fuenzalida M, Inestrosa NC (2014) In vivo activation of Wnt signaling pathway enhances cognitive function of adult mice and reverses cognitive deficits in an Alzheimer’s disease model. J Neurosci 34:2191–2202. https://doi.org/10.1523/JNEUROSCI.0862-13.2014

    Article  CAS  PubMed  Google Scholar 

  98. Inestrosa NC, Arenas E (2010) Emerging roles of Wnts in the adult nervous system. Nat Rev Neurosci 11:77–86. https://doi.org/10.1038/nrn2755

    Article  CAS  PubMed  Google Scholar 

  99. Willert K, Nusse R (2012) Wnt proteins. Cold Spring Harb Perspect Biol 4:a007864. https://doi.org/10.1101/cshperspect.a007864

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Komiya Y, Habas R (2008) Wnt signal transduction pathways. Organogenesis 4:68–75

    Article  Google Scholar 

  101. MacDonald BT, Tamai K, He X (2009) Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 17:9–26. https://doi.org/10.1016/j.devcel.2009.06.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Varela-nallar L, Alfaro IE, Serrano FG et al (2010) Wingless-type family member 5A (Wnta-5a) stimulates synaptic differentiation and function of glutamatergic synapses. Proc Natl Acad Sci U S A 107:10–15. https://doi.org/10.1073/pnas.1010011107 DCSupplemental.www.pnas.org/cgi/doi/10.1073/pnas.1010011107

    Article  Google Scholar 

  103. Filippone MG, Di Palma T, Lucci V, Zannini M (2014) Pax8 modulates the expression of Wnt4 that is necessary for the maintenance of the epithelial phenotype of thyroid cells. BMC Mol Biol 15:21. https://doi.org/10.1186/1471-2199-15-21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Pasca di Magliano M, Di Lauro R, Zannini M (2000) Pax8 has a key role in thyroid cell differentiation. Proc Natl Acad Sci U S A 97:13144–13149. https://doi.org/10.1073/pnas.240336397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Miller LD, Park KS, Guo QM, Alkharouf NW, Malek RL, Lee NH, Liu ET, Cheng SY (2001) Silencing of Wnt signaling and activation of multiple metabolic pathways in response to thyroid hormone-stimulated cell proliferation. Mol Cell Biol 21:6626–6639. https://doi.org/10.1128/MCB.21.19.6626-6639.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Guigon CJ, Zhao L, Lu C, Willingham MC, Cheng SY (2008) Regulation of beta-catenin by a novel nongenomic action of thyroid hormone beta receptor. Mol Cell Biol 28:4598–4608. https://doi.org/10.1128/MCB.02192-07

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. O’Shea PJ, Kim DW, Logan JG et al (2012) Advanced bone formation in mice with a dominant-negative mutation in the thyroid hormone receptor β gene due to activation of Wnt/β-catenin protein signaling. J Biol Chem 287:17812–17822. https://doi.org/10.1074/jbc.M111.311464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Rosenfeld CS (2016) Sex­specific placental responses in fetal. Development 156:3422–3434. https://doi.org/10.1210/en.2015

    Article  Google Scholar 

  109. Cvoro A, Devito L, Milton FA, Noli L, Zhang A, Filippi C, Sakai K, Suh JH et al (2015) A thyroid hormone receptor/KLF9 axis in human hepatocytes and pluripotent stem cells. Stem Cells 33:416–428. https://doi.org/10.1002/stem.1875

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Chew L-J, Shen W, Ming X, Senatorov VV, Chen HL, Cheng Y, Hong E, Knoblach S et al (2011) SRY-box containing gene 17 regulates the Wnt/-catenin signaling pathway in oligodendrocyte progenitor cells. J Neurosci 31:13921–13935. https://doi.org/10.1523/JNEUROSCI.3343-11.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the Basal Center of Excellence in Aging and Regeneration (CONICYT-AFB 170005) to N.C.I., FONDECYT (no. 1160724) to N.C.I., and FONDECYT (no. 11160651) to P.C. We also thank our special grant “Lithium in Health and Disease” from the Sociedad Química y Minera de Chile (SQM).

Author information

Author notes

  1. Paulina Salazar and Pedro Cisternas contributed equally to this work.

Authors and Affiliations

  1. Centro de Envejecimiento y Regeneración (CARE UC), Departamento de Biología Celular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile

    Paulina Salazar, Pedro Cisternas, Milka Martinez & Nibaldo C. Inestrosa

  2. Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia

    Nibaldo C. Inestrosa

  3. Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Punta Arenas, Chile

    Nibaldo C. Inestrosa

  4. CARE UC Biomedical Research Center, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Av. Bernardo O’Higgins 340, P. O. Box 114, -D, Santiago, Chile

    Nibaldo C. Inestrosa

Authors
  1. Paulina Salazar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pedro Cisternas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Milka Martinez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nibaldo C. Inestrosa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nibaldo C. Inestrosa.

Ethics declarations

Conflicts of Interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Salazar, P., Cisternas, P., Martinez, M. et al. Hypothyroidism and Cognitive Disorders during Development and Adulthood: Implications in the Central Nervous System. Mol Neurobiol 56, 2952–2963 (2019). https://doi.org/10.1007/s12035-018-1270-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-018-1270-y

Keywords

Search

Navigation