Skip to main content
SpringerLink
Log in

Activation of Liver X Receptor Is Protective Against Ethanol-Induced Developmental Impairment of Bergmann Glia and Purkinje Neurons in the Mouse Cerebellum

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Cerebellar Purkinje cell and granule cell development are coordinated by Bergmann glia, and are particularly sensitive to ethanol (EtOH) exposure. The liver X receptor (LXR) plays important roles in Bergmann glial development. However, the effect of LXR activation on EtOH-mediated impairment of Bergmann glia and subsequently on Purkinje cell dendritogenesis remains undetermined. Therefore, using immunohistochemistry, quantitative real-time PCR and Western blot, we tested the possible protection of LXR agonist T0901317 (T0) on Bergmann glia and Purkinje cell dendritogenesis in mice exposed to ethanol. Results showed that a brief exposure of EtOH on postnatal day (PD 5) significantly decreased the average body weight of mice at PD 6 without alteration in the brain weight. In EtOH-exposed mice, the number of migrating granule cells in the molecular layer was significantly decreased, and this effect was attenuated by pretreatment of T0. EtOH exposure also resulted in the significant reduction of calbindin-labeled Purkinje cells, their maximum dendrite length, and impairment of Purkinje cell dendritogenesis. Furthermore, EtOH induced the activation of microglia in the Purkinje cell layer and impaired the development of Bergmann glia. However, pretreatment of T0 effectively blocked all of these responses. These responses were found to be mediated by the inhibition of upregulated levels of β-catenin and transcription factor LEF1 in the cerebellum. Overall, the results suggest that activating LXRs on postnatal mice exposed to EtOH is protective to Bergmann glia, and thus may play a critical role in preventing EtOH-induced defects during cerebellar development.

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
Fig. 8

Similar content being viewed by others

References

  1. González-Burgos I, Alejandre-Gómez M (2005) Cerebellar granule cell and Bergmann glial cell maturation in the rat is disrupted by pre-and post-natal exposure to moderate levels of ethanol. Int J Dev Neurosci 23(4):383–388

    Article  PubMed  Google Scholar 

  2. Charness ME (1993) Brain lesions in alcoholics. Alcohol Clin Exp Res 17(1):2–11

    Article  CAS  PubMed  Google Scholar 

  3. Maier SE, West JR (2001) Regional differences in cell loss associated with binge-like alcohol exposure during the first two trimesters equivalent in the rat. Alcohol (Fayetteville, NY) 23(1):49

    Article  CAS  Google Scholar 

  4. Sakata-Haga H, Sawada K, Hisano S, Fukui Y (2001) Abnormalities of cerebellar foliation in rats prenatally exposed to ethanol. Acta Neuropathol 102(1):36–40

    CAS  PubMed  Google Scholar 

  5. Nowoslawski L, Klocke BJ, Roth KA (2005) Molecular regulation of acute ethanol-induced neuron apoptosis. J Neuropathol Exp Neurol 64(6):490–497

    CAS  PubMed  Google Scholar 

  6. Olney JW, Young C, Wozniak DF, Jevtovic-Todorovic V, Ikonomidou C (2004) Do pediatric drugs cause developing neurons to commit suicide? Trends Pharmacol Sci 25(3):135–139

    Article  CAS  PubMed  Google Scholar 

  7. Goodlett CR, Eilers AT (1997) Alcohol-induced Purkinje cell loss with a single binge exposure in neonatal rats: a stereological study of temporal windows of vulnerability. Alcohol Clin Exp Res 21(4):738–744

    CAS  PubMed  Google Scholar 

  8. Hamre KM, West JR (1993) The effects of the timing of ethanol exposure during the brain growth spurt on the number of cerebellar Purkinje and granule cell nuclear profiles. Alcohol Clin Exp Res 17(3):610–622

    Article  CAS  PubMed  Google Scholar 

  9. Hatten ME (1999) Central nervous system neuronal migration. Annu Rev Neurosci 22(1):511–539

    Article  CAS  PubMed  Google Scholar 

  10. Xu HW, Yang Y, Tang XT, Zhao MN, Liang FC, Xu P, Hou BK, Xing Y, Bao XH, Fan XT (2013) Bergmann glia function in granule cell migration during cerebellum development. Mol Neurobiol 47(3):833–844

    Article  CAS  PubMed  Google Scholar 

  11. Rakic P (1971) Neuron–glia relationship during granule cell migration in developing cerebellar cortex. A Golgi and electonmicroscopic study in Macacus rhesus. J Comp Neurol 141(3):283–312

    Article  CAS  PubMed  Google Scholar 

  12. Rakic P, Sidman RL (1973) Organization of cerebellar cortex secondary to deficit of granule cells in weaver mutant mice. J Comp Neurol 152(2):133–161

    Article  CAS  PubMed  Google Scholar 

  13. Lippman JJ, Lordkipanidze T, Buell ME, Yoon SO, Dunaevsky A (2008) Morphogenesis and regulation of Bergmann glial processes during Purkinje cell dendritic spine ensheathment and synaptogenesis. Glia 56(13):1463–1477

    Article  PubMed Central  PubMed  Google Scholar 

  14. Lordkipanidze T, Dunaevsky A (2005) Purkinje cell dendrites grow in alignment with Bergmann glia. Glia 51(3):229–234

    Article  PubMed  Google Scholar 

  15. Ge WP, Yang XJ, Zhang Z, Wang HK, Shen W, Deng QD, Duan S (2006) Long-term potentiation of neuron–glia synapses mediated by Ca2+−permeable AMPA receptors. Sci Signal 312(5779):1533

    CAS  Google Scholar 

  16. Takatsuru Y, Takayasu Y, Iino M, Nikkuni O, Ueda Y, Tanaka K, Ozawa S (2006) Roles of glial glutamate transporters in shaping EPSCs at the climbing fiber-Purkinje cell synapses. Neurosci Res 54(2):140

    Article  CAS  PubMed  Google Scholar 

  17. Takayasu Y, Iino M, Shimamoto K, Tanaka K, Ozawa S (2006) Glial glutamate transporters maintain one-to-one relationship at the climbing fiber–Purkinje cell synapse by preventing glutamate spillover. J Neurosci 26(24):6563–6572

    Article  CAS  PubMed  Google Scholar 

  18. Cui W, Allen ND, Skynner M, Gusterson B, Clark AJ (2001) Inducible ablation of astrocytes shows that these cells are required for neuronal survival in the adult brain. Glia 34(4):272–282

    Article  CAS  PubMed  Google Scholar 

  19. Pérez-Torrero E, Durán P, Granados L, Gutiérrez-Ospina G, Cintra L, Dı́az-Cintra S (1997) Effects of acute prenatal ethanol exposure on Bergmann glia cells early postnatal development. Brain Res 746(1):305–308

    Article  PubMed  Google Scholar 

  20. Yamada K, Watanabe M (2002) Cytodifferentiation of Bergmann glia and its relationship with Purkinje cells. Anat Sci Int 77(2):94–108

    Article  PubMed  Google Scholar 

  21. Archer A, Lauter G, Hauptmann G, Mode A, Gustafsson JÅ (2008) Transcriptional activity and developmental expression of liver X receptor (lxr) in zebrafish. Dev Dyn 237(4):1090–1098

    Article  CAS  PubMed  Google Scholar 

  22. Teboul M, Enmark E, Li Q, Wikström A, Pelto-Huikko M, Gustafsson J (1995) OR-1, a member of the nuclear receptor superfamily that interacts with the 9-cis-retinoic acid receptor. Proc Natl Acad Sci 92(6):2096–2100

    Article  CAS  PubMed  Google Scholar 

  23. Fan X, Kim HJ, Bouton D, Warner M, Gustafsson JA (2008) Expression of liver X receptor beta is essential for formation of superficial cortical layers and migration of later-born neurons. Proc Natl Acad Sci U S A 105(36):13445–13450

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Xing Y, Fan XT, Ying DJ (2010) Liver X receptor agonist treatment promotes the migration of granule neurons during cerebellar development. J Neurochem 115(6):1486–1494

    Article  CAS  PubMed  Google Scholar 

  25. Pöschl JGD, Dorostkar MM, Kretzschmar HA, Schüller U (2013) Constitutive activation of β-catenin in neural progenitors results in disrupted proliferation and migration of neurons within the central nervous system. Dev Biol 374(2):319–332

    Article  PubMed  Google Scholar 

  26. Uno S, Endo K, Jeong Y, Kawana K, Miyachi H, Hashimoto Y, Makishima M (2009) Suppression of β-catenin signaling by liver X receptor ligands. Biochem Pharmacol 77(2):186–195

    Article  CAS  PubMed  Google Scholar 

  27. Dikranian K, Qin Y-Q, Labruyere J, Nemmers B, Olney JW (2005) Ethanol-induced neuroapoptosis in the developing rodent cerebellum and related brain stem structures. Dev Brain Res 155(1):1–13

    Article  CAS  Google Scholar 

  28. Taranukhin AG, Taranukhina EY, Saransaari P, Podkletnova IM, Pelto-Huikko M, Oja SS (2010) Neuroprotection by taurine in ethanol-induced apoptosis in the developing cerebellum. J Biomed Sci 17(Suppl 1):S12

    Article  PubMed  Google Scholar 

  29. Li ZF, Gao CY, Huang HQ, Sun WZ, Yi HL, Fan XT, Xu HW (2010) Neurotransmitter phenotype differentiation and synapse formation of neural precursors engrafting in amyloid-beta(1-40) injured rat hippocampus. J Alz Dis 21(4):1233–1247

    Google Scholar 

  30. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods 25(4):402–408

    Article  CAS  PubMed  Google Scholar 

  31. Eiraku M, Tohgo A, Ono K, Kaneko M, Fujishima K, Hirano T, Kengaku M (2005) DNER acts as a neuron-specific Notch ligand during Bergmann glial development. Nat Neurosci 8(7):873–880

    Article  CAS  PubMed  Google Scholar 

  32. Yamada K, Fukaya M, Shibata T, Kurihara H, Tanaka K, Inoue Y, Watanabe M (2000) Dynamic transformation of Bergmann glial fibers proceeds in correlation with dendritic outgrowth and synapse formation of cerebellar Purkinje cells. J Comp Neurol 418(1):106–120

    Article  CAS  PubMed  Google Scholar 

  33. Weyer A, Schilling K (2003) Developmental and cell type-specific expression of the neuronal marker NeuN in the murine cerebellum. J Neurosci Res 73(3):400–409

    Article  CAS  PubMed  Google Scholar 

  34. Willert K, Nusse R (1998) β-catenin: a key mediator of Wnt signaling. Curr Opin Genet Dev 8(1):95–102

    Article  CAS  PubMed  Google Scholar 

  35. Riikonen J, Jaatinen P, Rintala J, Pörsti I, Karjala K, Hervonen A (2002) Intermittent ethanol exposure increases the number of cerebellar microglia. Alcohol and Alcohol 37(5):421–426

    Article  CAS  Google Scholar 

  36. Grosche J, Matyash V, Möller T, Verkhratsky A, Reichenbach A, Kettenmann H (1999) Microdomains for neuron–glia interaction: parallel fiber signaling to Bergmann glial cells. Nat Neurosci 2(2):139–143

    Article  CAS  PubMed  Google Scholar 

  37. Iino M, Goto K, Kakegawa W, Okado H, Sudo M, Ishiuchi S, Miwa A, Takayasu Y, Saito I, Tsuzuki K (2001) Glia-synapse interaction through Ca2+−permeable AMPA receptors in Bergmann glia. Sci Signal 292(5518):926

    CAS  Google Scholar 

  38. Selvadurai HJ, Mason JO (2011) Wnt/β-catenin signalling is active in a highly dynamic pattern during development of the mouse cerebellum. PLoS One 6(8):e23012

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Wang X, Imura T, Sofroniew MV, Fushiki S (2011) Loss of adenomatous polyposis coli in Bergmann glia disrupts their unique architecture and leads to cell nonautonomous neurodegeneration of cerebellar Purkinje neurons. Glia 59(6):857–868

    Article  PubMed Central  PubMed  Google Scholar 

  40. Makoukji J, Meffre D, Grenier J, Liere P, Lobaccaro J-MA, Schumacher M, Massaad C (2011) Interplay between LXR and Wnt/β-catenin signaling in the negative regulation of peripheral myelin genes by oxysterols. J Neurosci 31(26):9620–9629

    Article  CAS  PubMed  Google Scholar 

  41. Chuu C-P (2011) Modulation of liver X receptor signaling as a prevention and therapy for colon cancer. Med Hypotheses 76(5):697–699

    Article  CAS  PubMed  Google Scholar 

  42. Shackleford GG, Makoukji J, Grenier J, Liere P, Meffre D, Massaad C (2013) Differential regulation of Wnt/beta-catenin signaling by liver X receptors in Schwann cells and oligodendrocytes. Biochem Pharmacol 86(1):106–114

    Article  CAS  PubMed  Google Scholar 

  43. Tiwari V, Chopra K (2013) Resveratrol abrogates alcohol-induced cognitive deficits by attenuating oxidative-nitrosative stress and inflammatory cascade in the adult rat brain. Neurochem Int 62(6):861–869

    Article  CAS  PubMed  Google Scholar 

  44. Crews F, Nixon K, Kim D, Joseph J, Shukitt–Hale B, Qin L, Zou J (2006) BHT blocks NF-κB activation and ethanol-induced brain damage. Alcohol Clin Exp Res 30(11):1938–1949

    Article  CAS  PubMed  Google Scholar 

  45. Shirpoor A, Salami S, Khadem-Ansari MH, Minassian S, Yegiazarian M (2009) Protective effect of vitamin E against ethanol-induced hyperhomocysteinemia, DNA damage, and atrophy in the developing male rat brain. Alcohol Clin Exp Res 33(7):1181–1186

    Article  CAS  PubMed  Google Scholar 

  46. Tiwari V, Chopra K (2012) Attenuation of oxidative stress, neuroinflammation, and apoptosis by curcumin prevents cognitive deficits in rats postnatally exposed to ethanol. Psychopharmacology 224(4):519–535

    Article  CAS  PubMed  Google Scholar 

  47. Xu P, Li D, Tang X, Bao X, Huang J, Tang Y, Yang Y, Xu H, Fan X (2013) LXR agonists: new potential therapeutic drug for neurodegenerative diseases. Mol Neurobiol. doi:10.1007/s12035-013-8461-3

    Google Scholar 

  48. Zhang-Gandhi CX, Drew PD (2007) Liver X receptor and retinoid X receptor agonists inhibit inflammatory responses of microglia and astrocytes. J Neuroimmunol 183(1):50–59

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Marı́n-Teva JL, Dusart I, Colin C, Gervais A, van Rooijen N, Mallat M (2004) Microglia promote the death of developing Purkinje cells. Neuron 41(4):535–547

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the National Nature Science Foundation of China (no. 31070927 and no. 31071299) and the Foundation of the Third Military Medical University (no. 2011XQN05).

Author information

Authors and Affiliations

  1. Department of Histology and Embryology, Third Military Medical University, Chongqing, 400038, People’s Republic of China

    Yang Yang, Meina Zhao, Dayu Sun, Xiaotong Tang & Xiaotang Fan

  2. Southwest Eye Hospital, Southwest Hospital, Third Military Medical University, Chongqing, 400038, People’s Republic of China

    Yongping Tang & Haiwei Xu

  3. Key Laboratory of Visual Damage and Regeneration and Restoration of Chongqing, Chongqing, 400038, People’s Republic of China

    Yongping Tang & Haiwei Xu

  4. Institute of Immunology, PLA, Third Military Medical University, Chongqing, 400038, People’s Republic of China

    Yan Xing & Yuzhang Wu

  5. Department of Anesthesiology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400038, People’s Republic of China

    Xiaohang Bao

Authors
  1. Yang Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yongping Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yan Xing
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Meina Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaohang Bao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dayu Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiaotong Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yuzhang Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Haiwei Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xiaotang Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Haiwei Xu or Xiaotang Fan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yang, Y., Tang, Y., Xing, Y. et al. Activation of Liver X Receptor Is Protective Against Ethanol-Induced Developmental Impairment of Bergmann Glia and Purkinje Neurons in the Mouse Cerebellum. Mol Neurobiol 49, 176–186 (2014). https://doi.org/10.1007/s12035-013-8510-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-013-8510-y

Keywords

Search

Navigation