Skip to main content
SpringerLink
Log in

Similar distribution changes of GABAergic interneuron subpopulations in contrast to the different impact on neurogenesis between developmental and adult-stage hypothyroidism in the hippocampal dentate gyrus in rats

  • Reproductive Toxicology
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

Abstract

Hypothyroidism affects neurogenesis. The present study was performed to clarify the sensitivity of neurogenesis-related cellular responses in the hippocampal dentate gyrus between developmental and adult-stage hypothyroidism. An exposure study of methimazole (MMI) as an anti-thyroid agent at 0, 50, 200 ppm in the drinking water was performed using pregnant rats from gestation day 10 to postnatal day (PND) 21 (developmental hypothyroidism) and adult male rats by setting an identical exposure period from PND 46 through to PND 77 (adult-stage hypothyroidism). Offspring with developmental hypothyroidism were killed at PND 21 or PND 77, and animals with adult-stage hypothyroidism were killed at PND 77. Proliferation and apoptosis were unchanged in the dentate subgranular zone by either developmental or adult-stage hypothyroidism. With regard to precursor granule cells, a sustained reduction of paired box 6-positive stem or early progenitor cells and a transient reduction of doublecortin-positive late-stage progenitor cells were observed after developmental hypothyroidism with MMI at 50 and 200 ppm. These cells were unchanged by adult-stage hypothyroidism. With regard to γ-aminobutyric acid (GABA) ergic interneuron subpopulations in the dentate hilus, the number of parvalbumin-positive cells was decreased and the number of calretinin-positive cells was increased after both developmental and adult-stage hypothyroidism with MMI at 50 and 200 ppm. Fluctuations in GABAergic interneuron numbers with developmental hypothyroidism continued through to PND 77 with 200 ppm MMI. Considering the roles of GABAergic interneuron subpopulations in neurogenesis and neuronal differentiation, subpopulation changes in GABAergic interneurons by hypothyroidism may be the signature of aberrant neurogenesis even at the adult stage.

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

Similar content being viewed by others

Abbreviations

ADHD:

Attention deficit and hyperactivity disorder

Calb2:

Calretinin

C T :

Threshold cycle

Dcx:

Doublecortin

GABA:

γ-Aminobutyric acid

GD:

Gestational day

Hprt:

Hypoxanthine-guanine phosphoribosyltransferase

MMI:

Methimazole

Pax6:

Paired box 6

PCNA:

Proliferating cell nuclear antigen

PND:

Postnatal day

Pvalb:

Parvalbumin

PTU:

6-propyl-2-thiouracil

SD:

Sprague–Dawley

SGZ:

Subgranular zone

T3 :

Triiodothyronine

T4 :

Thyroxine

TH:

Thyroid hormone

TSH:

Thyroid-stimulating hormone

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick end labeling

References

  • Akaike M, Kato N, Ohno H, Kobayashi T (1991) Hyperactivity and spatial maze learning impairment of adult rats with temporary neonatal hypothyroidism. Neurotoxicol Teratol 13:317–322

    Article  PubMed  CAS  Google Scholar 

  • Almeida C, Brasil MA, Costa AJ, Reis FA, Reuters V, Teixeira P, Ferreira M, Marques AM, Melo BA, Teixeira LB, Buescu A, Vaisman M (2007) Subclinical hypothyroidism: psychiatric disorders and symptoms. Rev Bras Psiquiatr 29:157–159

    Article  PubMed  Google Scholar 

  • Ambrogini P, Cuppini R, Ferri P, Mancini C, Ciaroni S, Voci A, Gerdoni E, Gallo G (2005) Thyroid hormones affect neurogenesis in the dentate gyrus of adult rat. Neuroendocrinology 81:244–253

    Article  PubMed  CAS  Google Scholar 

  • Berbel P, Marco P, Cerezo JR, DeFelipe J (1996) Distribution of parvalbumin immunoreactivity in the neocortex of hypothyroid adult rats. Neurosci Lett 204:65–68

    Article  PubMed  CAS  Google Scholar 

  • Bernal J, Nunez J (1995) Thyroid hormones and brain development. Eur J Endocrinol 133:390–398

    Article  PubMed  CAS  Google Scholar 

  • Breunig JJ, Silbereis J, Vaccarino FM, Sestan N, Rakic P (2007) Notch regulates cell fate and dendrite morphology of newborn neurons in the postnatal dentate gyrus. Proc Natl Acad Sci USA 104:20558–20563

    Article  PubMed  CAS  Google Scholar 

  • Choi JH, Yoo KY, Lee CH, Yi SS, Yoo DY, Seong JK, Yoon YS, Hwang IK, Won MH (2011) Effects of treadmill exercise combined with MK 801 treatment on neuroblast differentiation in the dentate gyrus in rats. Cell Mol Neurobiol 31:285–292

    Article  PubMed  CAS  Google Scholar 

  • Delange F (2000) The role of iodine in brain development. Proc Nutr Soc 59:75–79

    Article  PubMed  CAS  Google Scholar 

  • Desouza LA, Ladiwala U, Daniel SM, Agashe S, Vaidya RA, Vaidya VA (2005) Thyroid hormone regulates hippocampal neurogenesis in the adult rat brain. Mol Cell Neurosci 29:414–426

    Article  PubMed  CAS  Google Scholar 

  • Duveau V, Laustela S, Barth L, Gianolini F, Vogt KE, Keist R, Chandra D, Homanics GE, Rudolph U, Fritschy JM (2011) Spatiotemporal specificity of GABAA receptor-mediated regulation of adult hippocampal neurogenesis. Eur J Neurosci 34:362–373

    Article  PubMed  Google Scholar 

  • Eriksson PS, Perfilieva E, Björk-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH (1998) Neurogenesis in the adult human hippocampus. Nat Med 4:1313–1317

    Article  PubMed  CAS  Google Scholar 

  • Gilbert ME, Sui L, Walker MJ, Anderson W, Thomas S, Smoller SN, Schon JP, Phani S, Goodman JH (2007) Thyroid hormone insufficiency during brain development reduces parvalbumin immunoreactivity and inhibitory function in the hippocampus. Endocrinology 148:92–102

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • Goodman JH, Gilbert ME (2007) Modest thyroid hormone insufficiency during development induces a cellular malformation in the corpus callosum: a model of cortical dysplasia. Endocrinology 148:2593–2597

    Article  PubMed  CAS  Google Scholar 

  • Gulyás AI, Hájos N, Freund TF (1996) Interneurons containing calretinin are specialized to control other interneurons in the rat hippocampus. J Neurosci 16:3397–3411

    PubMed  Google Scholar 

  • Gulyás AI, Buzsáki G, Freund TF, Hirase H (2006) Populations of hippocampal inhibitory neurons express different levels of cytochrome c. Eur J Neurosci 23:2581–2594

    Article  PubMed  Google Scholar 

  • Hodge RD, Kowalczyk TD, Wolf SA, Encinas JM, Rippey C, Enikolopov G, Kempermann G, Hevner RF (2008) Intermediate progenitors in adult hippocampal neurogenesis: Tbr2 expression and coordinate regulation of neuronal output. J Neurosci 28:3707–3717

    Article  PubMed  CAS  Google Scholar 

  • Houser CR (2007) Interneurons of the dentate gyrus: an overview of cell types, terminal fields and neurochemical identity. Prog Brain Res 163:217–232

    Article  PubMed  CAS  Google Scholar 

  • Hwang IK, Yoo KY, Yoo DY, Choi JH, Lee CH, Kang IJ, Kwon DY, Kim YS, Kim DW, Won MH (2011) Zizyphus enhances cell proliferation and neuroblast differentiation in the subgranular zone of the dentate gyrus in middle-aged mice. J Med Food 14:195–200

    Article  PubMed  CAS  Google Scholar 

  • Kapoor R, Ghosh H, Nordstrom K, Vennstrom B, Vaidya VA (2011) Loss of thyroid hormone receptor β is associated with increased progenitor proliferation and NeuroD positive cell number in the adult hippocampus. Neurosci Lett 487:199–203

    Article  PubMed  CAS  Google Scholar 

  • Knoth R, Singec I, Ditter M, Pantazis G, Capetian P, Meyer RP, Horvat V, Volk B, Kempermann G (2010) Murine features of neurogenesis in the human hippocampus across the lifespan from 0 to 100 years. PLoS ONE 5:e8809

    Article  PubMed  Google Scholar 

  • 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  PubMed  CAS  Google Scholar 

  • Lee KY, Shibutani M, Inoue K, Kuroiwa K, U M, Woo GH, Hirose M (2006) Methacarn fixation—effects of tissue processing and storage conditions on detection of mRNAs and proteins in paraffin-embedded tissues. Anal Biochem 351:36–43

    Google Scholar 

  • Lavado-Autric R, Ausó E, García-Velasco JV, Arufe Mdel C, Escobar del Rey F, Berbel P, Morreale de Escobar G (2003) Early maternal hypothyroxinemia alters histogenesis and cerebral cortex cytoarchitecture of the progeny. J Clin Invest 111:1073–1082

    PubMed  CAS  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the \( 2^{{ - \Updelta \Updelta C_{\text{T}} }} \) method. Methods 25:402–408

  • Masiulis I, Yun S, Eisch AJ (2011) The interesting interplay between interneurons and adult hippocampal neurogenesis. Mol Neurobiol. doi:10.1007/s12035-011-8207-z

  • Montero-Pedrazuela A, Venero C, Lavado-Autric R, Fernández-Lamo I, García-Verdugo JM, Bernal J, Guadaño-Ferraz A (2006) Modulation of adult hippocampal neurogenesis by thyroid hormones: implications in depressive-like behavior. Mol Psychiatry 11:361–371

    Article  PubMed  CAS  Google Scholar 

  • Nam SM, Yoo DY, Kim W, Yoo M, Kim DW, Won MH, Hwang IK, Yoon YS (2011) Effects of s-allyl-l-cysteine on cell proliferation and neuroblast differentiation in the mouse dentate gyrus. J Vet Med Sci 73:1071–1075

    Article  PubMed  CAS  Google Scholar 

  • Negishi T, Kawasaki K, Sekiguchi S, Ishii Y, Kyuwa S, Kuroda Y, Yoshikawa Y (2005) Attention-deficit and hyperactive neurobehavioural characteristics induced by perinatal hypothyroidism in rats. Behav Brain Res 159:323–331

    Article  PubMed  CAS  Google Scholar 

  • Pineda-Reynoso M, Cano-Europa E, Blas-Valdivia V, Hernandez-Garcia A, Franco-Colin M, Ortiz-Butron R (2010) Hypothyroidism during neonatal and perinatal period induced by thyroidectomy of the mother causes depressive-like behavior in prepubertal rats. Neuropsychiatr Dis Treat 6:137–143

    PubMed  Google Scholar 

  • Saegusa Y, Woo GH, Fujimoto H, Kemmochi S, Shimamoto K, Hirose M, Mitsumori K, Nishikawa A, Shibutani M (2010) Sustained production of Reelin-expressing interneurons in the hippocampal dentate hilus after developmental exposure to anti-thyroid agents in rats. Reprod Toxicol 29:407–414

    Article  PubMed  CAS  Google Scholar 

  • Sait Gönen M, Kisakol G, Savas Cilli A, Dikbas O, Gungor K, Inal A, Kaya A (2004) Assessment of anxiety in subclinical thyroid disorders. Endocr J 51:311–315

    Article  PubMed  Google Scholar 

  • Schoonover CM, Seibel MM, Jolson DM, Stack MJ, Rahman RJ, Jones SA, Mariash CN, Anderson GW (2004) Thyroid hormone regulates oligodendrocyte accumulation in developing rat brain white matter tracts. Endocrinology 145:5013–5020

    Article  PubMed  CAS  Google Scholar 

  • Shibutani M, Woo GH, Fujimoto H, Saegusa Y, Takahashi M, Inoue K, Hirose M, Nishikawa A (2009) Assessment of developmental effects of hypothyroidism in rats from in utero and lactation exposure to anti-thyroid agents. Reprod Toxicol 28:297–307

    Article  PubMed  CAS  Google Scholar 

  • Tozuka Y, Fukuda S, Namba T, Seki T, Hisatsune T (2005) GABAergic excitation promotes neuronal differentiation in adult hippocampal progenitor cells. Neuron 47:803–815

    Article  PubMed  CAS  Google Scholar 

  • Venero C, Guadaño-Ferraz A, Herrero AI, Nordström K, Manzano J, de Escobar GM, Bernal J, Vennström B (2005) Anxiety, memory impairment, and locomotor dysfunction caused by a mutant thyroid hormone receptor α1 can be ameliorated by T3 treatment. Genes Dev 19:2152–2163

    Article  PubMed  CAS  Google Scholar 

  • Vermiglio F, Lo Presti VP, Moleti M, Sidoti M, Tortorella G, Scaffidi G, Castagna MG, Mattina F, Violi MA, Crisà A, Artemisia A, Trimarchi F (2004) Attention deficit and hyperactivity disorders in the offspring of mothers exposed to mild-moderate iodine deficiency: a possible novel iodine deficiency disorder in developed countries. J Clin Endocrinol Metab 89:6054–6060

    Article  PubMed  CAS  Google Scholar 

  • Wallis K, Sjögren M, van Hogerlinden M, Silberberg G, Fisahn A, Nordström K, Larsson L, Westerblad H, Morreale de Escobar G, Shupliakov O, Vennström B (2008) Locomotor deficiencies and aberrant development of subtype-specific GABAergic interneurons caused by an unliganded thyroid hormone receptor α1. J Neurosci 28:1904–1915

    Article  PubMed  CAS  Google Scholar 

  • Yan BC, Yoo KY, Park JH, Lee CH, Choi JH, Won MH (2011) The high dosage of earthworm (Eisenia andrei) extract decreases cell proliferation and neuroblast differentiation in the mouse hippocampal dentate gyrus. Anat Cell Biol 44:218–225

    Article  PubMed  Google Scholar 

  • Yoo DY, Kim W, Kim DW, Yoo KY, Chung JY, Youn HY, Yoon YS, Choi SY, Won MH, Hwang IK (2011) Pyridoxine enhances cell proliferation and neuroblast differentiation by upregulating the GABAergic system in the mouse dentate gyrus. Neurochem Res 36:713–721

    Article  PubMed  CAS  Google Scholar 

  • Zhang L, Blomgren K, Kuhn HG, Cooper-Kuhn CM (2009) Effects of postnatal thyroid hormone deficiency on neurogenesis in the juvenile and adult rat. Neurobiol Dis 34:366–374

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Mrs. Shigeko Suzuki for her technical assistance in preparing the histological specimens. This work was supported by a grant from Ministry of Economy, Trade and Industry (METI), Japan.

Conflict of interest

All authors disclose that there are no conflicts of interest that could inappropriately influence the outcome of the present study.

Author information

Authors and Affiliations

  1. Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo, 183-8509, Japan

    Ayako Shiraki, Hirotoshi Akane, Takumi Ohishi, Liyun Wang, Reiko Morita, Kazuhiko Suzuki, Kunitoshi Mitsumori & Makoto Shibutani

Authors
  1. Ayako Shiraki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hirotoshi Akane
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takumi Ohishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Liyun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Reiko Morita
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kazuhiko Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kunitoshi Mitsumori
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Makoto Shibutani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Makoto Shibutani.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 898 kb)

Supplementary material 2 (PDF 101 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shiraki, A., Akane, H., Ohishi, T. et al. Similar distribution changes of GABAergic interneuron subpopulations in contrast to the different impact on neurogenesis between developmental and adult-stage hypothyroidism in the hippocampal dentate gyrus in rats. Arch Toxicol 86, 1559–1569 (2012). https://doi.org/10.1007/s00204-012-0846-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00204-012-0846-y

Keywords

Search

Navigation