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Cellular and Molecular Neurobiology

, Volume 33, Issue 4, pp 513–520 | Cite as

Increased Density of Dystrophin Protein in the Lateral Versus the Vermal Mouse Cerebellum

  • Wanda M. Snow
  • Mark Fry
  • Judy E. AndersonEmail author
Original Research

Abstract

Dystrophin, present in muscle, also resides in the brain, including cerebellar Purkinje neurons. The cerebellum, although historically associated with motor abilities, is also implicated in cognition. An absence of brain dystrophin in Duchenne muscular dystrophy (DMD) and in the mdx mouse model results in cognitive impairments. Localization studies of cerebellar dystrophin, however, have focused on the vermal cerebellum, associated with motor function, and have not investigated dystrophin distribution in the lateral cerebellum, considered to mediate cognitive function. The present study examined dystrophin localization in vermal and lateral cerebellar regions and across subcellular areas of Purkinje neurons in the mouse using immunohistochemistry. In both vermal and lateral cerebellum, dystrophin was restricted to puncta on somatic and dendritic membranes of Purkinje neurons. The density of dystrophin puncta was greater in the lateral than the vermal region. Neither the size of puncta nor the area of Purkinje neuron somata differed between regions. Results support the view that cognitive deficits in the DMD and the mdx model may be mediated by the loss of dystrophin, particularly in the lateral cerebellum. Findings have important implications for future studies examining the neurophysiological sequelae of neuronal dystrophin deficiency and the role of the lateral cerebellum in cognition.

Keywords

Purkinje neurons Dendrites Quantification Morphometry Immunohistochemistry 

Notes

Acknowledgments

This research was supported by an operating Grant from Manitoba Institute for Child Health (JEA and MF) and a Postgraduate Scholarship from the Natural Sciences and Engineering Research Council (WMS). The funders did not contribute to the study design, interpretation, or manuscript preparation. The authors wish to thank Ms. R. Upadhaya and Dr. W. Mizunoya (Kyushu University) for advice with cryosectioning and immunostaining and Dr. James Hare for assistance with the statistical analysis.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

Supplementary material 1 (MPG 92 kb)

Supplementary material 2 (MPG 116 kb)

Supplementary material 3 (MPG 174 kb)

Supplementary material 4 (MPG 50 kb)

10571_2013_9917_MOESM5_ESM.docx (14 kb)
Supplementary material 5 (DOCX 14 kb)

References

  1. Allen G, Buxton RB, Wong EC, Courchesne E (1997) Attentional activation of the cerebellum independent of motor involvement. Science 275:1940–1943PubMedCrossRefGoogle Scholar
  2. Anderson JL, Head SI, Morley JW (2003) Altered inhibitory input to Purkinje cells of dystrophin-deficient mice. Brain Res 982:280–283PubMedCrossRefGoogle Scholar
  3. Anderson JL, Head SI, Morley JW (2004) Long-term depression is reduced in cerebellar Purkinje cells of dystrophin-deficient mdx mice. Brain Res 1019:289–292PubMedCrossRefGoogle Scholar
  4. Blake DJ, Hawkes R, Benson MA, Beesley PW (1999) Different dystrophin-like complexes are expressed in neurons and glia. J Cell Biol 147:645–658PubMedCrossRefGoogle Scholar
  5. Chen SH, Desmond JE (2005) Cerebrocerebellar networks during articulatory rehearsal and verbal working memory tasks. Neuroimage 24:332–338PubMedCrossRefGoogle Scholar
  6. Cotton S, Voudouris NJ, Greenwood KM (2001) Intelligence and Duchenne muscular dystrophy: full-scale, verbal, and performance intelligence quotients. Dev Med Child Neurol 43:497–501PubMedCrossRefGoogle Scholar
  7. Cyrulnik SE, Hinton VJ (2008) Duchenne muscular dystrophy: a cerebellar disorder? Neurosci Biobehav Rev 32:486–496PubMedCrossRefGoogle Scholar
  8. Dorman C, Hurley AD, D’Avignon J (1988) Language and learning disorders in older boys with Duchenne muscular dystrophy. Dev Med Child Neurol 30:316–327PubMedCrossRefGoogle Scholar
  9. Fatemi SH, Aldinger KA, Ashwood P, Bauman ML, Blaha CD, Blatt GJ, Chauhan A, Chauhan V, Dager SR, Dickson PE, Estes AM, Goldowitz D, Heck DH, Kemper TL, King BH, Martin LA, Millen KJ, Mittleman G, Mosconi MW, Persico AM, Sweeney JA, Webb SJ, Welsh JP (2012) Consensus paper: pathological role of the cerebellum in autism. Cerebellum 11:777–807Google Scholar
  10. Fulbright RK, Jenner AR, Mencl WE, Pugh KR, Shaywitz BA, Shaywitz SE, Frost SJ, Skudlarski P, Constable RT, Lacadie CM, Marchione KE, Gore JC (1999) The cerebellum’s role in reading: a functional MR imaging study. AJNR Am J Neuroradiol 20:1925–1930Google Scholar
  11. Hendriksen JG, Vles JS (2008) Neuropsychiatric disorders in males with Duchenne muscular dystrophy: frequency rate of attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder, and obsessive–compulsive disorder. J Child Neurol 23:477–481PubMedCrossRefGoogle Scholar
  12. Hinton VJ, Cyrulnik SE, Fee RJ, Batchelder A, Kiefel JM, Goldstein EM, Kaufmann P, De Vivo DC (2009) Association of autistic spectrum disorders with dystrophinopathies. Pediatr Neurol 41:339–346PubMedCrossRefGoogle Scholar
  13. Huard J, Tremblay JP (1992) Localization of dystrophin in the Purkinje cells of normal mice. Neurosci Lett 137:105–108PubMedCrossRefGoogle Scholar
  14. Huard J, Satoh A, Tremblay JP (1992) Mosaic expression of dystrophin in the cerebellum of heterozygote dystrophic (mdx) mice. Neuromuscul Disord 2:311–321PubMedCrossRefGoogle Scholar
  15. Jancsik V, Hajos F (1998) Differential distribution of dystrophin in postsynaptic densities of spine synapses. NeuroReport 9:2249–2251PubMedCrossRefGoogle Scholar
  16. Joyal CC, Meyer C, Jacquart G, Mahler P, Caston J, Lalonde R (1996) Effects of midline and lateral cerebellar lesions on motor coordination and spatial orientation. Brain Res 739:1–11PubMedCrossRefGoogle Scholar
  17. Joyal CC, Strazielle C, Lalonde R (2001) Effects of dentate nucleus lesions on spatial and postural sensorimotor learning in rats. Behav Brain Res 122:131–137PubMedCrossRefGoogle Scholar
  18. Kim TW, Wu K, Black IB (1995) Deficiency of brain synaptic dystrophin in human Duchenne muscular dystrophy. Ann Neurol 38:446–449PubMedCrossRefGoogle Scholar
  19. Knuesel I, Mastrocola M, Zuellig RA, Bornhauser B, Schaub MC, Fritschy JM (1999) Short communication: altered synaptic clustering of GABAA receptors in mice lacking dystrophin (mdx mice). Eur J Neurosci 11:4457–4462PubMedCrossRefGoogle Scholar
  20. Knuesel I, Zuellig RA, Schaub MC, Fritschy JM (2001) Alterations in dystrophin and utrophin expression parallel the reorganization of GABAergic synapses in a mouse model of temporal lobe epilepsy. Eur J Neurosci 13:1113–1124PubMedCrossRefGoogle Scholar
  21. Kueh SL, Head SI, Morley JW (2008) GABA(A) receptor expression and inhibitory post-synaptic currents in cerebellar Purkinje cells in dystrophin-deficient mdx mice. Clin Exp Pharmacol Physiol 35:207–210PubMedGoogle Scholar
  22. Kueh SL, Dempster J, Head SI, Morley JW (2011) Reduced postsynaptic GABAA receptor number and enhanced gaboxadol induced change in holding currents in Purkinje cells of the dystrophin-deficient mdx mouse. Neurobiol Dis 43:558–564PubMedCrossRefGoogle Scholar
  23. Lalonde R, Strazielle C (2003) The effects of cerebellar damage on maze learning in animals. Cerebellum 2:300–309PubMedCrossRefGoogle Scholar
  24. Leggio MG, Molinari M, Neri P, Graziano A, Mandolesi L, Petrosini L (2000) Representation of actions in rats: the role of cerebellum in learning spatial performances by observation. Proc Natl Acad Sci USA 97:2320–2325PubMedCrossRefGoogle Scholar
  25. Leibowitz D, Dubowitz V (1981) Intellect and behaviour in Duchenne muscular dystrophy. Dev Med Child Neurol 23:577–590PubMedCrossRefGoogle Scholar
  26. Lidov HG, Byers TJ, Watkins SC, Kunkel LM (1990) Localization of dystrophin to postsynaptic regions of central nervous system cortical neurons. Nature 348:725–728PubMedCrossRefGoogle Scholar
  27. Lidov HG, Byers TJ, Kunkel LM (1993) The distribution of dystrophin in the murine central nervous system: an immunocytochemical study. Neuroscience 54:167–187PubMedCrossRefGoogle Scholar
  28. Martin LA, Goldowitz D, Mittleman G (2003) The cerebellum and spatial ability: dissection of motor and cognitive components with a mouse model system. Eur J Neurosci 18:2002–2010PubMedCrossRefGoogle Scholar
  29. Marvel CL, Desmond JE (2010) Functional topography of the cerebellum in verbal working memory. Neuropsychol Rev 20:271–279PubMedCrossRefGoogle Scholar
  30. McKay BE, Molineux ML, Turner RW (2004) Biotin is endogenously expressed in select regions of the rat central nervous system. J Comp Neurol 473:86–96PubMedCrossRefGoogle Scholar
  31. Moukhles H, Carbonetto S (2001) Dystroglycan contributes to the formation of multiple dystrophin-like complexes in brain. J Neurochem 78:824–834PubMedCrossRefGoogle Scholar
  32. Muntoni F, Mateddu A, Serra G (1991) Passive avoidance behaviour deficit in the mdx mouse. Neuromuscul Disord 1:121–123PubMedCrossRefGoogle Scholar
  33. Nyberg-Hansen R, Horn J (1972) Functional aspects of cerebellar signs in clinical neurology. Acta Neurol Scand Suppl 51:219–245PubMedGoogle Scholar
  34. Ogasawara A (1989) Downward shift in IQ in persons with Duchenne muscular dystrophy compared to those with spinal muscular atrophy. Am J Ment Retard 93:544–547PubMedGoogle Scholar
  35. Perronnet C, Vaillend C (2010) Dystrophins, utrophins, and associated scaffolding complexes: role in mammalian brain and implications for therapeutic strategies. J Biomed Biotechnol 2010:849426PubMedGoogle Scholar
  36. Petersen SE, Fox PT, Posner MI, Mitten M, Raichle ME (1989) Positron emission tomographic studies of the processing of single words. J Cognitive Neurosci 1:153–170CrossRefGoogle Scholar
  37. Pilgram GS, Potikanond S, Baines RA, Fradkin LG, Noordermeer JN (2010) The roles of the dystrophin-associated glycoprotein complex at the synapse. Mol Neurobiol 41:1–21PubMedCrossRefGoogle Scholar
  38. Ryding E, Decety J, Sjoholm H, Stenberg G, Ingvar DH (1993) Motor imagery activates the cerebellum regionally. A SPECT rCBF study with 99mTc-HMPAO. Brain Res Cogn Brain Res 1:94–99PubMedCrossRefGoogle Scholar
  39. Sillitoe RV, Benson MA, Blake DJ, Hawkes R (2003) Abnormal dysbindin expression in cerebellar mossy fiber synapses in the mdx mouse model of Duchenne muscular dystrophy. J Neurosci 23:6576–6585PubMedGoogle Scholar
  40. Uchino M, Teramoto H, Naoe H, Yoshioka K, Miike T, Ando M (1994a) Localisation and characterisation of dystrophin in the central nervous system of controls and patients with Duchenne muscular dystrophy. J Neurol Neurosurg Psychiatry 57:426–429PubMedCrossRefGoogle Scholar
  41. Uchino M, Yoshioka K, Miike T, Tokunaga M, Uyama E, Teramoto H, Naoe H, Ando M (1994b) Dystrophin and dystrophin-related protein in the brains of normal and mdx mice. Muscle Nerve 17:533–538PubMedCrossRefGoogle Scholar
  42. Vaillend C, Rendon A, Misslin R, Ungerer A (1995) Influence of dystrophin-gene mutation on mdx mouse behavior. I. Retention deficits at long delays in spontaneous alternation and bar-pressing tasks. Behav Genet 25:569–579PubMedCrossRefGoogle Scholar
  43. Vaillend C, Billard JM, Laroche S (2004) Impaired long-term spatial and recognition memory and enhanced CA1 hippocampal LTP in the dystrophin-deficient Dmd (mdx) mouse. Neurobiol Dis 17:10–20PubMedCrossRefGoogle Scholar
  44. Vajnerova O, Zhuravin IA, Brozek G (2000) Functional ablation of deep cerebellar nuclei temporarily impairs learned coordination of forepaw and tongue movements. Behav Brain Res 108:189–195PubMedCrossRefGoogle Scholar
  45. Villarreal RP, Steinmetz JE (2005) Neuroscience and learning: lessons from studying the involvement of a region of cerebellar cortex in eyeblink classical conditioning. J Exp Anal Behav 84:631–652PubMedCrossRefGoogle Scholar
  46. Whelan TB (1987) Neuropsychological performance of children with Duchenne muscular dystrophy and spinal muscle atrophy. Dev Med Child Neurol 29:212–220PubMedCrossRefGoogle Scholar
  47. Wu JY, Kuban KC, Allred E, Shapiro F, Darras BT (2005) Association of Duchenne muscular dystrophy with autism spectrum disorder. J Child Neurol 20:790–795PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of PsychologyUniversity of ManitobaWinnipegCanada
  2. 2.Department of Biological SciencesFaculty of Science, University of ManitobaWinnipegCanada

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