Skip to main content
SpringerLink
Log in

Developmental Hypothyroxinemia and Hypothyroidism Reduce Parallel Fiber–Purkinje Cell Synapses in Rat Offspring by Downregulation of Neurexin1/Cbln1/GluD2 Tripartite Complex

  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

Abstract

Iodine is a significant micronutrient. Iodine deficiency (ID)-induced hypothyroxinemia and hypothyroidism during developmental period can cause cerebellar dysfunction. However, mechanisms are still unclear. Therefore, the present research aims to study effects of developmental hypothyroxinemia caused by mild ID and hypothyroidism caused by severe ID or methimazole (MMZ) on parallel fiber–Purkinje cell (PF-PC) synapses in filial cerebellum. Maternal hypothyroxinemia and hypothyroidism models were established in Wistar rats using ID diet and deionized water supplemented with different concentrations of potassium iodide or MMZ water. Birth weight and cerebellum weight were measured. We also examined PF-PC synapses using immunofluorescence, and western blot analysis was conducted to investigate the activity of Neurexin1/cerebellin1 (Cbln1)/glutamate receptor d2 (GluD2) tripartite complex. Our results showed that hypothyroxinemia and hypothyroidism decreased birth weight and cerebellum weight and reduced the PF-PC synapses on postnatal day (PN) 14 and PN21. Accordingly, the mean intensity of vesicular glutamate transporter (VGluT1) and Calbindin immunofluorescence was reduced in mild ID, severe ID, and MMZ groups. Moreover, maternal hypothyroxinemia and hypothyroidism reduced expression of Neurexin1/Cbln1/GluD2 tripartite complex. Our study supports the hypothesis that developmental hypothyroxinemia and hypothyroidism reduce PF-PC synapses, which may be attributed to the downregulation of Neurexin1/Cbln1/GluD2 tripartite complex.

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
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Puig-Domingo M, Vila L (2013) The implications of iodine and its supplementation during pregnancy in fetal brain development. Curr Clin Pharmaco 8:97–109

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. 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  CAS  PubMed  Google Scholar 

  4. Glinoer G (2001) Potential consequences of maternal hypothyroidism on the offspring: evidence and implications. Horm Res 55:109–114

    Article  CAS  PubMed  Google Scholar 

  5. 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 

  6. Pearce EN, Andersson M, Zimmermann MB (2013) Global iodine nutrition: where do we stand in 2013? Thyroid 23:523–528

    Article  CAS  PubMed  Google Scholar 

  7. Skeaff SA (2011) Iodine deficiency in pregnancy: the effect on neurodevelopment in the child. Nutrients 3:265–273

    Article  PubMed  PubMed Central  Google Scholar 

  8. Lavado-Autric R, Ausó E, García-Velasco JV, et al. (2003) Early maternal hypothyroxinemia alters histogenesis and cerebral cortex cytoarchitecture of the progeny. J Clin Invest 111:1073–1082

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Pop VJ, Kuijpens JL, van Baar AL, et al. (1999) Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin Endocrinol 50:149–155

    Article  CAS  Google Scholar 

  10. Morreale de Escobar G, Obregon MJ, Escobar del Rey F (2000) Is neuropsychological development related to maternal hypothyroidism or to maternal hypothyroxinemia? J Clin Endocrinol Metab 85:3975–3987

    CAS  PubMed  Google Scholar 

  11. Morreale de Escobar G, Obregon MJ, Escobar del Rey F (2004) Role of thyroid hormone during early brain development. Eur J Endocrinol 151:U25–U37

    Article  CAS  PubMed  Google Scholar 

  12. Bath SC, Steer CD, Golding J, Emmett P, Rayman MP (2013) Effect of inadequate iodine status in UK pregnant women on cognitive outcomes in their children: results from the Avon Longitudinal Study of Parents and Children (ALSPAC). Lancet 382:331–337

    Article  CAS  PubMed  Google Scholar 

  13. Finken MJ, van Eijsden M, Loomans EM, Vrijkotte TG, Rotteveel J (2013) Maternal hypothyroxinemia in early pregnancy predicts reduced performance in reaction time tests in 5- to 6-year-old offspring. J Clin Endocrinol Metab 98:1417–1426

    Article  CAS  PubMed  Google Scholar 

  14. Brooks VB (1984) Cerebellar functions in motor control. Hum Neurobiol 2:251–260

    CAS  PubMed  Google Scholar 

  15. Hibi M, Shimizu T (2012) Development of the cerebellum and cerebellar neural circuits. Dev Neurobiol 72:282–301

    Article  PubMed  Google Scholar 

  16. Mishina M, Uemura T, Yasumura M, Yoshida T (2012) Molecular mechanism of parallel fiber-Purkinje cell synapse formation. Front Neural Circuits 6:90

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lee SJ, Uemura T, Yoshida T, Mishina M (2012) GluRδ2 assembles four neurexins into trans-synaptic triad to trigger synapse formation. J Neurosci 32:4688–4701

    Article  CAS  PubMed  Google Scholar 

  18. Kurihara H, Hashimoto K, Kano M, et al. (1997) Impaired parallel fiber–>Purkinje cell synapse stabilization during cerebellar development of mutant mice lacking the glutamate receptor delta2 subunit. J Neurosci 17:9613–9623

    CAS  PubMed  Google Scholar 

  19. Wang W, Nakadate K, Masugi-Tokita M, et al. (2014) Distinct cerebellar engrams in short-term and long-term motor learning. Proc Natl Acad Sci U S A 111:E188–E193

    Article  CAS  PubMed  Google Scholar 

  20. Rochefort C, Lefort JM, Rondi-Reig L (2013) The cerebellum: a new key structure in the navigation system. Front Neural Circuits 7:35

    Article  PubMed  PubMed Central  Google Scholar 

  21. Pregno G, Frola E, Graziano S, et al. (2013) Differential regulation of neurexin at glutamatergic and GABAergic synapses. Front Cell Neurosci 7:35

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Craig AM, Kang Y (2007) Neurexin-neuroligin signaling in synapse development. Curr Opin Neurobiol 17:43–52

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. De Wit J, Sylwestrak E, O'Sullivan ML, et al. (2009) LRRTM2 interacts with Neurexin1 and regulates excitatory synapse formation. Neuron 64:799–806

    Article  PubMed  PubMed Central  Google Scholar 

  24. Kavety B, Morgan JI (1998) Characterization of transcript processing of the gere encoding precerebellin-1. Brain Res Mol Brain Res 63:98–104

    Article  CAS  PubMed  Google Scholar 

  25. Yuzaki M (2011) Cbln1 and its family proteins in synapse formation and maintenance. Curr Opin Neurobiol 21:215–220

    Article  CAS  PubMed  Google Scholar 

  26. Hirai H, Pang Z, Bao D, et al. (2005) Cbln1 is essential for synaptic integrity and plasticity in the cerebellum. Nat Neurosci 8:1534–1541

    Article  CAS  PubMed  Google Scholar 

  27. Matsuda K, Yuzaki M (2011) Cbln family proteins promote synapse formation by regulating distinct neurexin signaling pathways in various brain regions. Eur J Neurosci 33:1447–1461

    Article  PubMed  Google Scholar 

  28. Yuzaki M (2009) New (but old) molecules regulating synapse integrity and plasticity: Cbln1 and the delta2 glutamate receptor. Neuroscience 162:633–643

    Article  CAS  PubMed  Google Scholar 

  29. Koibuchi N, Chin WW (2000) Thyroid hormone action and brain development. Trends Endocrinol Metab 11:123–128

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  31. Wang Y, Wang Y, Dong J, et al. (2014) Developmental hypothyroxinaemia and hypothyroidism limit dendritic growth of cerebellar Purkinje cells in rat offspring: involvement of microtubule-associated protein 2 (MAP2) and stathmin. Neuropathol Appl Neurobiol 40:398–415

    Article  CAS  PubMed  Google Scholar 

  32. Wang Y, Wang Y, Dong J, et al. (2014) Developmental hypothyroxinemia and hypothyroidism reduce proliferation of cerebellar granule neuron precursors in rat offspring by downregulation of the sonic hedgehog signaling pathway. Mol Neurobiol 49:1143–1152

    Article  CAS  PubMed  Google Scholar 

  33. Reeves PG, Nielsen FH, Fahey Jr GC (1993) AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. J Nutr 123:1939–1951

    CAS  PubMed  Google Scholar 

  34. Wang Y, Wei W, Wang Y, et al. (2013) Neurotoxicity of developmental hypothyroxinemia and hypothyroidism in rats: impairments of long-term potentiation are mediated by phosphatidylinositol 3-kinase signaling pathway. Toxicol Appl Pharmacol 271:257–265

    Article  CAS  PubMed  Google Scholar 

  35. Wei W, Wang Y, Wang Y, et al. (2013) Developmental hypothyroxinemia induced by maternal mild iodine deficiency delays hippocampal axonal growth in the rat offspring. J Neuroendocrinol 25:852–862

    Article  CAS  PubMed  Google Scholar 

  36. Duong L, Klitten LL, Møller RS, et al. (2012) Mutations in NRXN1 in a family multiply affected with brain disorders: NRXN1 mutations and brain disorders. Am J Med Genet B Neuropsychiatr Genet 159B:354–358

    Article  PubMed  Google Scholar 

  37. Elibol-Can B, Kilic E, Yuruker S, Jakubowska-Dogru E (2014) Investigation into the effects of prenatal alcohol exposure on postnatal spine development and expression of synaptophysin and PSD95 in rat hippocampus. Int J Dev Neurosci 33:106–114

    Article  CAS  PubMed  Google Scholar 

  38. Kimura-Kuroda J, Nagata I, Negishi-Kato M, Kuroda Y (2002) Thyroid hormone-dependent development of mouse cerebellar Purkinje cells in vitro. Brain Res Dev Brain Res 137:55–65

    Article  CAS  PubMed  Google Scholar 

  39. Rinaldo L, Hansel C (2010) Ataxias and cerebellar dysfunction: involvement of synaptic plasticity deficits? Funct Neurol 25:135–139

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Rowen L, Young J, Birditt B, et al. (2002) Analysis of the human neurexin genes: alternative splicing and the generation of protein diversity. Genomics 79:587–597

    Article  CAS  PubMed  Google Scholar 

  41. Tabuchi K, Südhof TC (2002) Structure and evolution of neurexin genes: insight into the mechanism of alternative splicing. Genomics 79:849–859

    Article  CAS  PubMed  Google Scholar 

  42. Matsuda K, Miura E, Miyazaki T, et al. (2010) Cbln1 is a ligand for an orphan glutamate receptor delta2,a bidirectional synapse organizer. Science 328:363–368

    Article  CAS  PubMed  Google Scholar 

  43. Ito-Ishida A, Miura E, Emi K, et al. (2008) Cbln1 regulates rapid formation and maintenance of excitatory synapses in mature cerebellar Purkinje cells in vitro and in vivo. J Neurosci 28:5920–5930

    Article  CAS  PubMed  Google Scholar 

  44. Miura E, Iijima T, Yuzaki M, Watanabe M (2006) Distinct expression of Cbln family Mrna in developing and adult mouse brains. Eur J Neurosci 24:750–760

    Article  PubMed  Google Scholar 

  45. Hirano T (2012) Glutamate-receptor-like molecule GluRδ2 involved in synapse formation at parallel fiber-Purkinje neuron synapses. Cerebellum 11:71–77

    Article  CAS  PubMed  Google Scholar 

  46. Cao J, Viholainen JI, Dart C, Warwick HK, Leyland ML, Courtney MJ (2005) The PSD95-nNOS interface: a target for inhibition of excitotoxic p38 stress-activated protein kinase activation and cell death. J Cell Biol 168:117–126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ehrlich I, Malinow R (2004) Postsynaptic density 95 controls AMPA receptor incorporation during long-term potentiation and experience-driven synaptic plasticity. J Neurosci 24:916–927

    Article  CAS  PubMed  Google Scholar 

  48. Garner CC, Nash J, Huganir RL (2000) PDZ domains in synapse assembly and signalling. Trends Cell Biol 10:274–280

    Article  CAS  PubMed  Google Scholar 

  49. Dong J, Wang Y, Wang Y, et al. (2013) Iodine deficiency increases apoptosis and decreases synaptotagmin-1 and PSD-95 in rat hippocampus. Nutr Neurosci 16:135–141

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by Important Platform of Science and Technology for the Universities in Liaoning Province (Grant number 16010) and Program for Liaoning Innovative Research Team in University (Grant number LT2015028).

Author’s Contributions

Jie Chen and Weiping Teng conceived and designed the study Yuan Wang, Jing Dong, Yi Wang, Wei Wei, Binbin Song performed the experiments. Weiping Teng and Jie Chen obtained funding and ethics approval. Yuan Wang, Jing Dong, Yi Wang, Zhongyan Shan and Jie Chen analyzed the data. Yuan Wang wrote the article in whole. Jing Dong, Yi Wang and Jie Chen revised the article.

Author information

Authors and Affiliations

  1. Department of Occupational and Environmental Health, School of Public Health, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, People’s Republic of China

    Yuan Wang, Jing Dong, Yi Wang, Wei Wei, Binbin Song & Jie Chen

  2. Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Hospital of China Medical University, Shenyang, People’s Republic of China

    Zhongyan Shan & Weiping Teng

Authors
  1. Yuan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wei Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Binbin Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhongyan Shan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Weiping Teng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jie Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jie Chen.

Ethics declarations

Conflict 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

Wang, Y., Dong, J., Wang, Y. et al. Developmental Hypothyroxinemia and Hypothyroidism Reduce Parallel Fiber–Purkinje Cell Synapses in Rat Offspring by Downregulation of Neurexin1/Cbln1/GluD2 Tripartite Complex. Biol Trace Elem Res 173, 465–474 (2016). https://doi.org/10.1007/s12011-016-0664-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12011-016-0664-9

Keywords

Search

Navigation