Skip to main content

Advertisement

SpringerLink
Log in

Brain Metabolite Changes in Subcortical Regions After Exposure to Cuprizone for 6 Weeks: Potential Implications for Schizophrenia

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Cuprizone is a copper chelating agent able to selectively damage the white matter in the mouse brain. Recent studies have reported behavioral abnormalities relevant to some of schizophrenia symptoms. While associating white matter damage to the behavioral abnormalities, these previous studies did not rule out the possible impairment in neuronal functions in cuprizone-exposed mice. The aim of this study was to examine brain metabolites of the cuprizone-exposed mice by proton magnetic resonance spectroscopy (1H-MRS). The examined brain regions were the caudoputamen, midbrain, and thalamus; these subcortical regions showed different susceptibilities to cuprizone in terms of demyelination and oligodendrocyte loss in previous studies. Young C57BL/6 mice were fed a standard rodent chow without or with cuprizone (0.2 %) for 6 weeks. At the end, open-field and Y-maze tests were performed to measure the emotional and cognitive behaviors of the animals, followed by 1H-MRS procedure to evaluate the brain metabolites. Cuprizone-exposure increased anxiety levels and impaired spatial working memory. The same treatment increased T2 signal intensity in the cerebral cortex, hippocampus, and caudoputamen, but not in the thalamus. Cuprizone-exposure decreased the concentrations of NAA and NAA+NAAG in caudoputamen, but not in thalamus and midbrain. It decreased levels of Cr+PCr, GPC+PCh and myo-inositol in all the three brain regions. These results provided neurochemical evidence for the impairment in neuronal functions by cuprizone treatment.

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

References

  1. Kesterson JW, Carlton WW (1970) Aqueductal stenosis as the cause of hydrocephalus in mice fed the substituted hydrazine, cuprizone. Exp Mol Pathol 13:281–294

    Article  CAS  PubMed  Google Scholar 

  2. Blakemore WF (1972) Observations on oligodendrocyte degeneration, the resolution of status spongiosus and remyelination in cuprizone intoxication in mice. J Neurocytol 1:413–426

    Article  CAS  PubMed  Google Scholar 

  3. Kesterson JW, Carlton WW (1971) Monoamine oxidase inhibition and the activity of other oxidative enzymes in the brains of mice fed cuprizone. Toxicol Appl Pharmacol 20:386–395

    Article  CAS  PubMed  Google Scholar 

  4. Hoppel CL, Tandler B (1973) Biochemical effects of cuprizone on mouse liver and heart mitochondria. Biochem Pharmacol 22:2311–2318

    Article  CAS  PubMed  Google Scholar 

  5. Venturini G (1973) Enzymic activities and sodium, potassium and copper concentrations in mouse brain and liver after cuprizone treatment in vivo. J Neurochem 21:1147–1151

    Article  CAS  PubMed  Google Scholar 

  6. Matsushima GK, Morell P (2001) The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system. Brain Pathol 11:107–116

    Article  CAS  PubMed  Google Scholar 

  7. Liebetanz D, Merkler D (2006) Effects of commissural de-and remyelination on motor skill behaviour in the cuprizone mouse model of multiple sclerosis. Exp Neurol 202:217–224

    Article  CAS  PubMed  Google Scholar 

  8. Franco-Pons N, Torrente M, Colomina MT, Vilella E (2007) Behavioral deficits in the cuprizone-induced murine model of demyelination/remyelination. Toxicol Lett 169:205–213

    Article  CAS  PubMed  Google Scholar 

  9. Xiao L, Xu H, Zhang Y, Wei Z, He J, Jiang W, Li X, Dyck L, Devon R, Deng Y (2008) Quetiapine facilitates oligodendrocyte development and prevents mice from myelin breakdown and behavioral changes. Mol Psychiatry 13:697–708

    Article  CAS  PubMed  Google Scholar 

  10. Zhang Y, Xu H, Jiang W, Xiao L, Yan B, He J, Wang Y, Bi X, Li X, Kong J (2008) Quetiapine alleviates the cuprizone-induced white matter pathology in the brain of C57BL/6 mouse. Schizophr Res 106:182–191

    Article  PubMed  Google Scholar 

  11. Makinodan M, Yamauchi T, Tatsumi K, Okuda H, Takeda T, Kiuchi K, Sadamatsu M, Wanaka A, Kishimoto T (2009) Demyelination in the juvenile period, but not in adulthood, leads to long-lasting cognitive impairment and deficient social interaction in mice. Prog Neuropsychopharmacol Biol Psychiatry 33:978–985

    Article  CAS  PubMed  Google Scholar 

  12. Xu H, Yang HJ, Zhang Y, Clough R, Browning R, Li XM (2009) Behavioral and neurobiological changes in C57BL/6 mice exposed to cuprizone. Behav Neurosci 123:418–429

    Article  CAS  PubMed  Google Scholar 

  13. Gregg JR, Herring NR, Naydenov AV, Hanlin RP, Konradi C (2009) Downregulation of oligodendrocyte transcripts is associated with impaired prefrontal cortex function in rats. Schizophr Res 113:277–287

    Article  PubMed Central  PubMed  Google Scholar 

  14. Davis KL, Stewart DG, Friedman JI, Buchsbaum M, Harvey PD, Hof PR, Buxbaum J, Haroutunian V (2003) White matter changes in schizophrenia: evidence for myelin-related dysfunction. Arch Gen Psychiatry 60:443–456

    Article  PubMed  Google Scholar 

  15. Port JD, Agarwal N (2011) MR spectroscopy in schizophrenia. J Magn Reson Imaging 34:1251–1261

    Article  PubMed  Google Scholar 

  16. Marsman A, van den Heuvel MP, Klomp DW, Kahn RS, Luijten PR, Hulshoff Pol HE (2013) Glutamate in schizophrenia: a focused review and meta-analysis of 1H-MRS studies. Schizophr Bull 39:120–129

    Article  PubMed Central  PubMed  Google Scholar 

  17. Fernando K, McLean M, Chard D, MacManus D, Dalton C, Miszkiel KA, Gordon RM, Plant GT, Thompson AJ, Miller DH (2004) Elevated white matter myo-inositol in clinically isolated syndromes suggestive of multiple sclerosis. Brain 127:1361–1369

    Article  CAS  PubMed  Google Scholar 

  18. Narayana PA (2005) Magnetic resonance spectroscopy in the monitoring of multiple sclerosis. J Neuroimaging 15:46S–57S

    Article  PubMed Central  PubMed  Google Scholar 

  19. Aboul-Enein F, Krššák M, Höftberger R, Prayer D, Kristoferitsch W (2010) Reduced NAA-levels in the NAWM of patients with MS is a feature of progression. A study with quantitative magnetic resonance spectroscopy at 3 Tesla. PLoS One 5:e11625. doi:10.1371/journal.pone.0011625

    Article  PubMed Central  PubMed  Google Scholar 

  20. Tezuka T, Tamura M, Kondo MA, Sakaue M, Okada K, Takemoto K, Fukunari A, Miwa K, Ohzeki H, Kano S, Yasumatsu H, Sawa A, Kajii Y (2013) Cuprizone short-term exposure: astrocytic IL-6 activation and behavioral changes relevant to psychosis. Neurobiol Dis 59:63–68

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Xuan Y, Yan G, Peng H, Wu R, Xu H (2014) Concurrent changes in (1)H MRS metabolites and antioxidant enzymes in the brain of C57BL/6 mouse short-termly exposed to cuprizone: possible implications for schizophrenia. Neurochem Int 69:20–27

    Article  CAS  PubMed  Google Scholar 

  22. Yang HJ, Wang H, Zhang Y, Xiao L, Clough RW, Browning R, Li XM, Xu H (2009) Region-specific susceptibilities to cuprizone-induced lesions in the mouse forebrain: implications for the pathophysiology of schizophrenia. Brain Res 1270:121–130

    Article  CAS  PubMed  Google Scholar 

  23. Dong HW (2007) Allen reference atlas: a digital color brain atlas of the C57BL/6j male mouse. Wiley, Sesttle

    Google Scholar 

  24. Merkler D, Boretius S, Stadelmann C, Ernsting T, Michaelis T, Frahm J, Brück W (2005) Multicontrast MRI of remyelination in the central nervous system. NMR Biomed 18:395–403

    Article  PubMed  Google Scholar 

  25. Provencher SW (2001) Automatic quantitation of localizedin vivo1H spectra with LCModel. NMR Biomed 14:260–264

    Article  CAS  PubMed  Google Scholar 

  26. Xu H, Yang HJ, McConomy B, Browning R, Li XM (2010) Behavioral and neurobiological changes in C57BL/6 mouse exposed to cuprizone: effects of antipsychotics. Front Behav Neurosci 4:8. doi:10.3389/fnbeh.2010.00008

    Article  PubMed Central  PubMed  Google Scholar 

  27. Xu H, Yang HJ, Rose GM, Li XM (2011) Recovery of behavioral changes and compromised white matter in C57BL/6 mice exposed to cuprizone: effects of antipsychotic drugs. Front Behav Neurosci 5:31. doi:10.3389/fnbeh.2011.00031

    Article  PubMed Central  PubMed  Google Scholar 

  28. Wang H, Li C, Wang H, Mei F, Liu Z, Shen HY, Xiao L (2013) Cuprizone-induced demyelination in mice: age-related vulnerability and exploratory behavior deficit. Neurosci Bull 29:251–259

    Article  PubMed  Google Scholar 

  29. Boretius S, Escher A, Dallenga T, Wrzos C, Tammer R, Brück W, Nessler S, Frahm J, Stadelmann C (2012) Assessment of lesion pathology in a new animal model of MS by multiparametric MRI and DTI. NeuroImage 59:2678–2688

    Article  PubMed  Google Scholar 

  30. Chandran P, Upadhyay J, Markosyan S, Lisowski A, Buck W, Chin CL, Fox G, Luo F, Day M (2012) Magnetic resonance imaging and histological evidence for the blockade of cuprizone-induced demyelination in C57BL/6 mice. Neuroscience 202:446–453. doi:10.1016/j.neuroscience.2011.10.051

    Article  CAS  PubMed  Google Scholar 

  31. Torkildsen Ø, Brunborg LA, Thorsen F, Mørk SJ, Stangel M, Myhr KM, Bø L (2009) Effects of dietary intervention on MRI activity, de- and remyelination in the cuprizone model for demyelination. Exp Neurol 215:160–166

    Article  CAS  PubMed  Google Scholar 

  32. Bardgett ME, Griffith MS, Foltz RF, Hopkins JA, Massie CM, O’Connell SM (2006) The effects of clozapine on delayed spatial alternation deficits in rats with hippocampal damage. Neurobiol Learn Mem 85:86–94

    Article  CAS  PubMed  Google Scholar 

  33. Li Y, Qin HQ, Chen OS, Wang JJ (2004) Behavioral and neurochemical effects of the intrahippocampal co-injection of beta-amyloid protein 1–40 and ibotenic acid in rats. Int J Neurosci 114:1521–1531

    Article  CAS  PubMed  Google Scholar 

  34. Wall PM, Messier C (2001) The hippocampal formation-orbitomedial prefrontal cortex circuit in the attentional control of active memory. Behav Brain Res 127:99–117

    Article  CAS  PubMed  Google Scholar 

  35. Xu H, Yang HJ, Rose GM (2012) Chronic haloperidol-induced spatial memory deficits accompany the upregulation of D1 and D2 receptors in the caudate putamen of C57BL/6 mouse. Life Sci 91:322–328

    Article  CAS  PubMed  Google Scholar 

  36. Sun SW, Liang HF, Trinkaus K, Cross AH, Armstrong RC, Song SK (2006) Noninvasive detection of cuprizone induced axonal damage and demyelination in the mouse corpus callosum. Magn Reson Med 55:302–308

    Article  PubMed  Google Scholar 

  37. Xie M, Tobin JE, Budde MD, Chen CI, Trinkaus K, Cross AH, McDaniel DP, Song SK, Armstrong RC (2010) Rostrocaudal analysis of corpus callosum demyelination and axon damage across disease stages refines diffusion tensor imaging correlations with pathological teatures. J Neuropathol Exp Neurol 69:704–716

    Article  PubMed Central  PubMed  Google Scholar 

  38. Moffett JR, Ross B, Arun P, Madhavarao CN, Namboodiri AM (2007) N-Acetylaspartate in the CNS: from neurodiagnostics to neurobiology. Prog Neurobiol 81:89–131

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Friston KJ (1999) Schizophrenia and the disconnection hypothesis. Acta Psychiatr Scand Suppl 99:68–79

    Article  Google Scholar 

  40. Xu H, Li XM (2011) White matter abnormalities and animal models examining a putative role of altered white matter in schizophrenia. Schizophr Res Treatment. doi:10.1155/2011/826976

    Google Scholar 

  41. Gogtay N, Giedd JN, Lusk L, Hayashi KM, Greenstein D, Vaituzis AC (2004) Dynamic mapping of human cortical development during childhood through early adulthood. Proc Natl Acad Sci USA 101:8174–8179

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Sowell ER, Trauner DA, Gamst A, Jernigan TL (2002) Development of cortical and subcortical brain structures in childhood and adolescence: a structural MRI study. Dev Med Child Neurol 44:4–16

    Article  PubMed  Google Scholar 

  43. Toga AW, Thompson PM, Sowell E (2006) Mapping brain maturation. Trends Neurosci 29:148–159

  44. Rothman DL (1994) 1H NMR studies of human brain metabolism and physiology. In: Gillies RJ (ed) NMR in physiology and biomedicine. Academic Press, San Diego, pp 353–372

    Chapter  Google Scholar 

  45. Modica-Napolitano JS, Renshaw PF (2004) Ethanolamine and phospho- rethanolamine inhibit mitochondrial function in vitro: implications for mitochondrial dysfunction hypothesis in depression and bipolar disorder. Biol Psychiatry 55:273–277

    Article  CAS  PubMed  Google Scholar 

  46. Ongür D, Prescot AP, Jensen JE, Cohen BM, Renshaw PF (2009) Creatine abnormalities in schizophrenia and bipolar disorder. Psychiatry Res 172:44–48

    Article  PubMed Central  PubMed  Google Scholar 

  47. Gangadhar BN, Jayakumar PN, Subbakrishna DK, Janakiramaiah N, Keshavan MS (2004) Basal ganglia high-energy phosphate metabolism in neuroleptic-naive patients with schizophrenia: a 31-phosphorus magnetic resonance spectroscopic study. Am J Psychiatry 161:1304–1306

    Article  CAS  PubMed  Google Scholar 

  48. Sung YH, Yurgelun-Todd DA, Shi XF, Kondo DG, Lundberg KJ, McGlade EC, Hellem TL, Huber RS, Fiedler KK, Harrell RE, Nickerson BR, Kim SE, Jeong EK, Renshaw PF (2013) Decreased frontal lobe phosphocreatine levels in meth- amphetamine users. Drug Alcohol Depend 129:102–109

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Chang L, Ernst T, Speck O, Grob CS (2005) Additive effects of HIV and chronic methamphetamine use on brain metabolite abnormalities. Am J Psychiatry 162:361–369

    Article  PubMed  Google Scholar 

  50. Sung YH, Cho SC, Hwang J, Kim SJ, Kim H, Bae S, Kim N, Chang KH, Daniels M, Renshaw PF, Lyoo IK (2007) Relationship between N-acetyl-aspartate in gray and white matter of abstinent methamphetamine abusers and their history of drug abuse: a proton magnetic resonance spectroscopy study. Drug Alcohol Depend 88:28–35

    Article  CAS  PubMed  Google Scholar 

  51. Taylor MJ, Schweinsburg BC, Alhassoon OM, Gongvatana A, Brown GG, Young-Casey C, Letendre SL, Grant I, HNRC Group (2007) Effects of human immunodeficiency virus and methamphetamine on cerebral metabolites measured with magnetic resonance spectroscopy. J Neurovirol 13:150–159

    Article  CAS  PubMed  Google Scholar 

  52. Sailasuta N, Abulseoud O, Hernandez M, Haghani P, Ross BD (2010) Metabolic abnormalities in abstinent methamphetamine dependent subjects. Subst Abuse 2010:9–20

    PubMed  Google Scholar 

  53. Chang L, Ernst T, Leonido-Yee M, Walot I, Singer E (1999) Cerebral metabolite abnormalities correlate with clinical severity of HIV-cognitive motor complex. Neurology 52:100–108

    Article  CAS  PubMed  Google Scholar 

  54. Srinivasan R, Sailasuta N, Hurd R, Nelson S, Pelletier D (2005) Evidence of elevated glutamate in multiple sclerosis using magnetic resonance spectroscopy at 3 T. Brain 128:1016–1025

    Article  PubMed  Google Scholar 

  55. Ross B, Bluml S (2001) Magnetic resonance spectroscopy of the human brain. Anat Rec 265:54–84

    Article  CAS  PubMed  Google Scholar 

  56. Videen JS, Michaelis T, Pinto P, Ross BD (1995) Human cerebral osmolytes during chronic hyponatremia. A proton magnetic resonance spectroscopy study. J Clin Invest 95:788–793

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Chang L, Friedman J, Ernst T, Zhong K, Tsopelas ND, Davis K (2007) Brain metabolite abnormalities in the white matter of elderly schizophrenic subjects: implication for glial dysfunction. Biol Psychiatry 62:1396–1404

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Tayoshi S, Sumitani S, Taniguchi K, Shibuya-Tayoshi S, Numata S, Iga J, Nakataki M, Ueno S, Harada M, Ohmori T (2009) Metabolite changes and gender differences in schizophrenia using 3-Tesla proton magnetic resonance spectroscopy (1H-MRS). Schizophr Res 108:69–77

    Article  PubMed  Google Scholar 

  59. Shimon H, Sobolev Y, Davidson M, Haroutunian V, Belmaker RH, Agam G (1998) Inositol levels are decreased in postmortem brain of schizophrenic patients. Biol Psychiatry 44:428–432

    Article  CAS  PubMed  Google Scholar 

  60. Rudkin TM, Arnold DL (1999) Proton magnetic resonance spectroscopy for the diagnosis and management of cerebral disorders. Arch Neurol 56:919–926

    Article  CAS  PubMed  Google Scholar 

  61. Moore GJ, Galloway MP (2002) Magnetic resonance spectroscopy: neurochemistry and treatment effects in affective disorders. Psychopharmacol Bull 36:5–23

    PubMed  Google Scholar 

  62. Kirov II, Patil V, Babb JS, Rusinek H, Herbert J, Gonen O (2009) MR spectroscopy indicates diffuse multiple sclerosis activity during remission. J Neurol Neurosurg Psychiatr 80:1330–1336

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. Ohrmann P, Siegmund A, Suslow T, Pedersen A, Spitzberg K, Kersting A, Rothermundt M, Arolt V, Heindel W, Pfleiderer B (2007) Cognitive impairment and in vivo metabolites in first-episode neuroleptic-naive and chronic medicated schizophrenic patients: a proton magnetic resonance spectroscopy study. J Psychiatr Res 41:625–634

    Article  PubMed  Google Scholar 

  64. Yoo SY, Yeon S, Choi CH, Kang DH, Lee JM, Shin NY, Jung WH, Choi JS, Jang DP, Kwon JS (2009) Proton magnetic resonance spectroscopy in subjects with high genetic risk of schizophrenia: investigation of anterior cingulate, dorsolateral prefrontal cortex and thalamus. Schizophr Res 111:86–93

    Article  PubMed  Google Scholar 

  65. Keshavan MS, Dick RM, Diwadkar VA, Montrose DM, Prasad KM, Stanley JA (2009) Striatal metabolic alterations in non-psychotic adolescent offspring at risk for schizophrenia: a 1H spectroscopy study. Schizophr Res 115:88–93

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported in part by a Grant from the National Natural Science Foundation of China (30930027) and a postdoctoral research fellowship (G.Y.) from Li Ka Shing foundation.

Author information

Authors and Affiliations

  1. Department of Radiology, Second Affiliated Hospital, Shantou University Medical College, Shantou, 515041, Guangdong, China

    Gen Yan, Zhuozhi Dai, Zhiwei Shen, Guishan Zhang & Renhua Wu

  2. Mental Health Center, Shantou University Medical College, Shantou, 515065, Guangdong, China

    Yinghua Xuan & Haiyun Xu

Authors
  1. Gen Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yinghua Xuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhuozhi Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhiwei Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Guishan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Haiyun Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Renhua Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Haiyun Xu or Renhua Wu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yan, G., Xuan, Y., Dai, Z. et al. Brain Metabolite Changes in Subcortical Regions After Exposure to Cuprizone for 6 Weeks: Potential Implications for Schizophrenia. Neurochem Res 40, 49–58 (2015). https://doi.org/10.1007/s11064-014-1464-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-014-1464-2

Keywords

Search

Navigation