Advertisement

Myelin Deficits Caused by Olig2 Deficiency Lead to Cognitive Dysfunction and Increase Vulnerability to Social Withdrawal in Adult Mice

  • Xianjun Chen
  • Fei Wang
  • Jingli Gan
  • Zhonghua Zhang
  • Xuejun Liang
  • Tao Li
  • Nanxin Huang
  • Xiaofeng Zhao
  • Feng Mei
  • Lan XiaoEmail author
Original Article
  • 48 Downloads

Abstract

Oligodendrocyte (OL) and myelin development are crucial for network integration and are associated with higher brain functions. Accumulating evidence has demonstrated structural and functional impairment of OLs and myelin in serious mental illnesses. However, whether these deficits contribute to the brain dysfunction or pathogenesis of such diseases still lacks direct evidence. In this study, we conditionally deleted Olig2 in oligodendroglial lineage cells (Olig2 cKO) and screened the behavioral changes in adult mice. We found that Olig2 ablation impaired myelin development, which further resulted in severe hypomyelination in the anterior cingulate cortex. Strikingly, Olig2 cKO mice exhibited an anxious phenotype, aberrant responses to stress, and cognitive deficits. Moreover, Olig2 cKO mice showed increased vulnerability to social avoidance under the mild stress of social isolation. Together, these results indicate that developmental deficits in OL and myelin lead to cognitive impairment and increase the risk of phenotypes reminiscent of mental illnesses.

Keywords

Oligodendrocyte Olig2 Hypomyelination Cognition Social withdrawal 

Notes

Acknowledgements

This work was supported by the National Natural Science Foundation of China (31671117).

Conflict of interest

The authors declare that they have no competing interests.

References

  1. 1.
    Pajevic S, Basser PJ, Fields RD. Role of myelin plasticity in oscillations and synchrony of neuronal activity. Neuroscience 2014, 276: 135–147.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Xiao L, Ohayon D, McKenzie IA, Sinclair-Wilson A, Wright JL, Fudge AD, et al. Rapid production of new oligodendrocytes is required in the earliest stages of motor-skill learning. Nat Neurosci 2016, 19: 1210–1217.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Fuster JM. Frontal lobe and cognitive development. J Neurocytol 2002, 31: 373–385.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Lee FS, Heimer H, Giedd JN, Lein ES, Sestan N, Weinberger DR, et al. Mental health. Adolescent mental health–opportunity and obligation. Science 2014, 346: 547–549.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Miller DJ, Duka T, Stimpson CD, Schapiro SJ, Baze WB, McArthur MJ, et al. Prolonged myelination in human neocortical evolution. Proc Natl Acad Sci U S A 2012, 109: 16480–16485.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Casey BJ, Getz S, Galvan A. The adolescent brain. Dev Rev 2008, 28: 62–77.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    de Hoz L, Simons M. The emerging functions of oligodendrocytes in regulating neuronal network behaviour. Bioessays 2015, 37: 60–69.CrossRefGoogle Scholar
  8. 8.
    Haroutunian V, Katsel P, Roussos P, Davis KL, Altshuler LL, Bartzokis G. Myelination, oligodendrocytes, and serious mental illness. Glia 2014, 62: 1856–1877.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Liu X, Lai Y, Wang X, Hao C, Chen L, Zhou Z, et al. A combined DTI and structural MRI study in medicated-naive chronic schizophrenia. Magn Reson Imaging 2014, 32: 1–8.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Friedman JI, Tang C, Carpenter D, Buchsbaum M, Schmeidler J, Flanagan L, et al. Diffusion tensor imaging findings in first-episode and chronic schizophrenia patients. Am J Psychiatry 2008, 165: 1024–1032.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Mauney SA, Pietersen CY, Sonntag KC, Woo TW. Differentiation of oligodendrocyte precursors is impaired in the prefrontal cortex in schizophrenia. Schizophr Res 2015, 169: 374–380.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Radu A, Hristescu G, Katsel P, Haroutunian V, Davis KL. Microarray database mining and cell differentiation defects in schizophrenia. Adv Exp Med Biol 2011, 696: 67–74.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Hyde TM, Ziegler JC, Weinberger DR. Psychiatric disturbances in metachromatic leukodystrophy. Insights into the neurobiology of psychosis. Arch Neurol 1992, 49: 401–406.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Feinstein A, Magalhaes S, Richard JF, Audet B, Moore C. The link between multiple sclerosis and depression. Nat Rev Neurol 2014, 10: 507–517.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Millan MJ, Agid Y, Brune M, Bullmore ET, Carter CS, Clayton NS, et al. Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy. Nat Rev Drug Discov 2012, 11: 141–168.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Muetzel RL, Mous SE, van der Ende J, Blanken LM, van der Lugt A, Jaddoe VW, et al. White matter integrity and cognitive performance in school-age children: A population-based neuroimaging study. Neuroimage 2015, 119: 119–128.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Perez-Iglesias R, Tordesillas-Gutierrez D, McGuire PK, Barker GJ, Roiz-Santianez R, Mata I, et al. White matter integrity and cognitive impairment in first-episode psychosis. Am J Psychiatry 2010, 167: 451–458.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Falkai P, Steiner J, Malchow B, Shariati J, Knaus A, Bernstein HG, et al. Oligodendrocyte and interneuron density in hippocampal subfields in schizophrenia and association of oligodendrocyte number with cognitive deficits. Front Cell Neurosci 2016, 10: 78.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Wang F, Yang YJ, Yang N, Chen XJ, Huang NX, Zhang J, et al. Enhancing oligodendrocyte myelination rescues synaptic loss and improves functional recovery after chronic hypoxia. Neuron 2018, 99: 689–701 e685.Google Scholar
  20. 20.
    Moghaddam B, Javitt D. From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology 2012, 37: 4–15.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Kantrowitz JT, Javitt DC. N-methyl-d-aspartate (NMDA) receptor dysfunction or dysregulation: the final common pathway on the road to schizophrenia? Brain Res Bull 2010, 83: 108–121.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Lappe-Siefke C, Goebbels S, Gravel M, Nicksch E, Lee J, Braun PE, et al. Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination. Nat Genet 2003, 33: 366–374.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Yue T, Xian K, Hurlock E, Xin M, Kernie SG, Parada LF, et al. A critical role for dorsal progenitors in cortical myelination. J Neurosci 2006, 26: 1275–1280.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Chen X, Zhang W, Li T, Guo Y, Tian Y, Wang F, et al. Impairment of oligodendroglia maturation leads to aberrantly increased cortical glutamate and anxiety-like behaviors in juvenile mice. Front Cell Neurosci 2015, 9: 467.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Chen X, Ku L, Mei R, Liu G, Xu C, Wen Z, et al. Novel schizophrenia risk factor pathways regulate FEZ1 to advance oligodendroglia development. Transl Psychiatry 2017, 7: 1293.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Xu P, Xu H, Tang X, Xu L, Wang Y, Guo L, et al. Liver X receptor beta is essential for the differentiation of radial glial cells to oligodendrocytes in the dorsal cortex. Mol Psychiatry 2014, 19: 947–957.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Clapcote SJ, Lipina TV, Millar JK, Mackie S, Christie S, Ogawa F, et al. Behavioral phenotypes of Disc1 missense mutations in mice. Neuron 2007, 54: 387–402.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Yu Y, Chen Y, Kim B, Wang H, Zhao C, He X, et al. Olig2 targets chromatin remodelers to enhancers to initiate oligodendrocyte differentiation. Cell 2013, 152: 248–261.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Hardy RJ, Friedrich VL, Jr. Progressive remodeling of the oligodendrocyte process arbor during myelinogenesis. Dev Neurosci 1996, 18: 243–254.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Jahn O, Tenzer S, Werner HB. Myelin proteomics: molecular anatomy of an insulating sheath. Mol Neurobiol 2009, 40: 55–72.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Bourin M, Petit-Demouliere B, Dhonnchadha BN, Hascoet M. Animal models of anxiety in mice. Fundam Clin Pharmacol 2007, 21: 567–574.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Yuii K, Suzuki M, Kurachi M. Stress sensitization in schizophrenia. Ann N Y Acad Sci 2007, 1113: 276–290.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Commons KG, Cholanians AB, Babb JA, Ehlinger DG. The rodent forced swim test measures stress-coping strategy, not depression-like behavior. ACS Chem Neurosci 2017, 8: 955–960.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Green MF. Cognitive impairment and functional outcome in schizophrenia and bipolar disorder. J Clin Psychiatry 2006, 67 Suppl 9: 3–8; discussion 36–42.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Geyer MA, Ellenbroek B. Animal behavior models of the mechanisms underlying antipsychotic atypicality. Prog Neuropsychopharmacol Biol Psychiatry 2003, 27: 1071–1079.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Lueptow LM. Novel object recognition test for the investigation of learning and memory in mice. J Vis Exp 2017.Google Scholar
  37. 37.
    Green MF, Horan WP, Lee J. Social cognition in schizophrenia. Nat Rev Neurosci 2015, 16: 620–631.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Moy SS, Nadler JJ, Perez A, Barbaro RP, Johns JM, Magnuson TR, et al. Sociability and preference for social novelty in five inbred strains: an approach to assess autistic-like behavior in mice. Genes Brain Behav 2004, 3: 287–302.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Chugani HT, Behen ME, Muzik O, Juhasz C, Nagy F, Chugani DC. Local brain functional activity following early deprivation: a study of postinstitutionalized Romanian orphans. Neuroimage 2001, 14: 1290–1301.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014, 511: 421–427.Google Scholar
  41. 41.
    Purcell SM, Moran JL, Fromer M, Ruderfer D, Solovieff N, Roussos P, et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature 2014, 506: 185–190.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Goudriaan A, de Leeuw C, Ripke S, Hultman CM, Sklar P, Sullivan PF, et al. Specific glial functions contribute to schizophrenia susceptibility. Schizophr Bull 2014, 40: 925–935.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Georgieva L, Moskvina V, Peirce T, Norton N, Bray NJ, Jones L, et al. Convergent evidence that oligodendrocyte lineage transcription factor 2 (OLIG2) and interacting genes influence susceptibility to schizophrenia. Proc Natl Acad Sci U S A 2006, 103: 12469–12474.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Mitkus SN, Hyde TM, Vakkalanka R, Kolachana B, Weinberger DR, Kleinman JE, et al. Expression of oligodendrocyte-associated genes in dorsolateral prefrontal cortex of patients with schizophrenia. Schizophr Res 2008, 98: 129–138.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Gibson EM, Purger D, Mount CW, Goldstein AK, Lin GL, Wood LS, et al. Neuronal activity promotes oligodendrogenesis and adaptive myelination in the mammalian brain. Science 2014, 344: 1252304.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Makinodan M, Rosen KM, Ito S, Corfas G. A critical period for social experience-dependent oligodendrocyte maturation and myelination. Science 2012, 337: 1357–1360.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Tomassy GS, Berger DR, Chen HH, Kasthuri N, Hayworth KJ, Vercelli A, et al. Distinct profiles of myelin distribution along single axons of pyramidal neurons in the neocortex. Science 2014, 344: 319–324.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Rivers LE, Young KM, Rizzi M, Jamen F, Psachoulia K, Wade A, et al. PDGFRA/NG2 glia generate myelinating oligodendrocytes and piriform projection neurons in adult mice. Nat Neurosci 2008, 11: 1392–1401.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Flurkey K, Currer JM. Pitfalls of animal model systems in ageing research. Best Pract Res Clin Endocrinol Metab 2004, 18: 407–421.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Poggi G, Boretius S, Mobius W, Moschny N, Baudewig J, Ruhwedel T, et al. Cortical network dysfunction caused by a subtle defect of myelination. Glia 2016, 64: 2025–2040.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Wang H, Li C, Mei F, Liu Z, Shen HY, Xiao L. Cuprizone-induced demyelination in mice: age-related vulnerability and exploratory behavior deficit. Neurosci Bull 2013, 29: 251–259.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Maas DA, Valles A, Martens GJM. Oxidative stress, prefrontal cortex hypomyelination and cognitive symptoms in schizophrenia. Transl Psychiatry 2017, 7: e1171.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Liu J, Dietz K, DeLoyht JM, Pedre X, Kelkar D, Kaur J, et al. Impaired adult myelination in the prefrontal cortex of socially isolated mice. Nat Neurosci 2012, 15: 1621–1623.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Zhou Y, Fan L, Qiu C, Jiang T. Prefrontal cortex and the dysconnectivity hypothesis of schizophrenia. Neurosci Bull 2015, 31: 207–219.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Dai H, Okuda H, Iwabuchi K, Sakurai E, Chen Z, Kato M, et al. Social isolation stress significantly enhanced the disruption of prepulse inhibition in mice repeatedly treated with methamphetamine. Ann N Y Acad Sci 2004, 1025: 257–266.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    McKenzie IA, Ohayon D, Li H, de Faria JP, Emery B, Tohyama K, et al. Motor skill learning requires active central myelination. Science 2014, 346: 318–322.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Shanghai Institutes for Biological Sciences, CAS 2019

Authors and Affiliations

  1. 1.Department of Histology and Embryology, Chongqing Key Laboratory of NeurobiologyArmy Medical University (Third Military Medical University)ChongqingChina
  2. 2.Department of PsychiatryMental Diseases Prevention and Treatment Institute of The People’s Liberation Army (PLA)JiaozuoChina
  3. 3.Institute of Life Sciences, College of Life and Environmental SciencesHangzhou Normal UniversityHangzhouChina

Personalised recommendations