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Neurocognitive Impairment in mdx Mice

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Abstract

Duchenne muscular dystrophy (DMD) is a neuromuscular disorder that affects muscles and also the brain, resulting in memory and behavioral problems. In the pathogenesis of DMD, inflammation is an important factor during the degenerative process. However, the involvement of the brain is still unclear. Therefore, the objective of this study is to evaluate the cognitive involvement, BDNF levels, cytokine levels through the levels of TNF-α and IL-1β, the myeloperoxidase (MPO) activity, and the expression of proteins postsynaptic density (PSD)-95 and synaptophysin in the brain of mdx mice. To this aim, we used adult mdx mice. It was observed that mdx mice presented deficits on the habituation, aversive, and object recognition memory. These animals also had a depression-like behavior and an anxiety-like behavior, a decrease of BDNF levels, an increase in the levels of TNF-α and IL-1β, an increase of MPO activity, and an overexpression of synaptophysin and PSD-95 in brain tissue. In conclusion, these data show that mdx mice possibly present a neuroinflammatory component and the involvement of synaptic proteins associated to memory storage and restoring process impairment as well as a depressive- and anxiety-like behavior.

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References

  1. Ram S (2017) Global muscular dystrophy research: a 25-year bibliometric perspective. Neurol India 65:993–1000

    PubMed  Google Scholar 

  2. Knuesel I, Bornhauser BC, Zuellig RA, Heller F, Schaub MC, Fritschy JM (2000) Differential expression of utrophin and dystrophin in CNS neurons: an insitu hybridization and immunohistochemical study. J Comp Neurol 422:594–611

    CAS  PubMed  Google Scholar 

  3. Rae MG, O’Malley D (2016) Cognitive dysfunction in Duchenne muscular dystrophy: a possible role for neuromodulatory immune molecules. J Neurophysiol 116:1304–1315

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Miranda R, Laroche S, Vaillend C (2016) Reduced neuronal density in the CA1 anterodorsal hippocampus of the mdx mouse. Neuromuscul Disord 26:775–781

    PubMed  Google Scholar 

  5. Comim CM, Cassol OJ Jr, Constantino LC, Constantino LS, Petronilho F, Tuon L, Vainzof M, Dal-Pizzol F et al (2009) Oxidative variables and antioxidant enzymes activities in the mdx mouse brain. Neurochem Int 55:802–805

    CAS  PubMed  Google Scholar 

  6. Tuon L, Comim CM, Fraga DB, Scaini G, Rezin GT, Baptista BR, Streck EL, Vainzof M et al (2010) Mitochondrial respiratory chain and creatine kinase activities in mdx mouse brain. Muscle Nerve 41:257–260

    CAS  PubMed  Google Scholar 

  7. Vaillend C, Chaussenot R (2017) Relationships linking emotional, motor, cognitive and GABAergic dysfunctions in dystrophin-deficient mdx mice. Hum Mol Genet 26:1041–1055

    CAS  PubMed  Google Scholar 

  8. Comim CM, Moraz T, Abreu I, Fraga DB, Ghedim FV, Mildner N, Tuon L, Vainzof M et al (2011) Reduction of acethylcolinesterase activity in the brain of mdx mice. Neuromuscul Disord 21:359–362

    PubMed  Google Scholar 

  9. Comim CM, Hoepers A, Ventura L, Freiberger V, Dominguini D, Mina F, Mendonça BP, Scaini G et al (2016) Activity of Krebs cycle enzymes in mdx mice. Muscle Nerve 53:91–95

    CAS  PubMed  Google Scholar 

  10. de Brouwer AP, Nabuurs SB, Verhaart IE, Oudakker AR, Hordijk R, Yntema HG, Hordijk-Hos JM, Voesenek K et al (2014) A 3-base pair deletion, c.9711_9713del, in DMD results in intellectual disability without muscular dystrophy. Eur J Hum Genet 22:480–485

    PubMed  Google Scholar 

  11. Snow WM, Anderson JE, Jakobson LS (2013) Neuropsychological and neurobehavioral functioning in Duchenne muscular dystrophy: a review. Neurosci Biobehav Rev 37:743–752

    PubMed  Google Scholar 

  12. Piccini G, Gazzellini S, D’Amico A, Pane M, Castelli E, Vicari S (2014) Developmental lag of visuospatial attention in Duchenne muscular dystrophy. Res Dev Disabil 14(36C):55–61

    Google Scholar 

  13. Felisari G, Martinelli Boneschi F, Bardoni A, Sironi M, Comi GP, Robotti M, Turconi AC, Lai M et al (2000) Loss of Dp140 dystrophin. Isoform and intellectual impairment in Duchenne dystrophy. Neurology 55:559–564

    CAS  PubMed  Google Scholar 

  14. Nardes F, Araujo AP, Ribeiro MG (2012) Mental retardation in Duchenne muscular dystrophy. J Pediatr 88:6–16

    Google Scholar 

  15. 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 17:10–20

    CAS  PubMed  Google Scholar 

  16. Muntoni F, Mateddu A, Serra G (1991) Passive avoidance behaviour deficit in the mdx mouse. Neuromuscul Disord 1:121–123

    CAS  PubMed  Google Scholar 

  17. de Paepe B, De Bleecker JL (2013) Cytokines and chemokines as regulators of skeletal muscle inflammation: presenting the case of Duchenne muscular dystrophy. Mediat Inflamm 1:540370

    Google Scholar 

  18. Porter JD, Khanna S, Kaminski HJ, Rao JS, Merriam AP, Richmonds CR, Leahy P, Li J et al (2002) A chronic inflammatory response dominates the skeletal muscle molecular signature in dystrophin-deficient mdx mice. Hum Mol Genet 11:263–272

    CAS  PubMed  Google Scholar 

  19. Comim CM, Mathia GB, Hoepers A, Tuon L, Kapczinski F, Dal-Pizzol F, Quevedo J, Rosa MI (2015) Neurotrophins, cytokines, oxidative parameters and functionality in progressive muscular dystrophies. An Acad Bras Cienc 87:1809–1818

    CAS  PubMed  Google Scholar 

  20. Kuru S, Inukai A, Kato T, Liang Y, Kimura S, Sobue G (2003) Expression of tumor necrosis factor-alpha in regenerating muscle fibers in inflammatory and non-inflammatory myopathies. Acta Neuropathol 105:217–224

    CAS  Google Scholar 

  21. Porreca E, Guglielmi MD, Uncini A, Di Gregorio P, Angelini A, Di Febbo C, Pierdomenico SD, Baccante G et al (1999) Haemostatic abnormalities, cardiac involvement and serum tumor necrosis factor levels in X-linked dystrophic patients. Thromb Haemost 81:543–546

    CAS  PubMed  Google Scholar 

  22. Evans NP, Misyak SA, Robertson JL, Bassaganya-Riera J, Grange RW (2009) Immune-mediated mechanisms potentially regulate the disease time-course of duchenne muscular dystrophy and provide targets for therapeutic intervention. PM R 1:755–768

    PubMed  PubMed Central  Google Scholar 

  23. Marin I, Kipnis J (2013) Learning and memory ... and the immune system. Learn Mem 20:601–606

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Nico B, Roncali L, Mangieri D, Ribatti D (2005) Blood-brain barrier alterations in MDX mouse, an animal model of the Duchenne muscular dystrophy. Curr Neurovasc Res 2:47–54

    CAS  PubMed  Google Scholar 

  25. Nico B, Corsi P, Ria R, Crivellato E, Vacca A, Roccaro AM, Mangieri D, Ribatti D et al (2006) Increased matrix-metalloproteinase-2 and matrix-metalloproteinase-9 expression in the brain of dystrophic mdx mouse. Neuroscience 140:835–848

    CAS  PubMed  Google Scholar 

  26. Pozzi D, Menna E, Canzi A, Desiato G, Mantovani C, Matteoli M (2018) The communication between the immune and nervous systems: the role of IL-1β in synaptopathies. Front Mol Neurosci 11:111

    PubMed  PubMed Central  Google Scholar 

  27. Leussis MP, Bolivar VJ (2006) Habituation in rodents: a review of behavior, neurobiology, and genetics. Neurosci Biobehav Rev 36:1045–1064

    Google Scholar 

  28. De Boer SF, Koolhaas JM (2003) Defensive burying in rodents: ethology, neurobiology and psychopharmacology. Eur J Pharmacol 463:145–161

    PubMed  Google Scholar 

  29. Cohena SJ, Stackman RW Jr (2015) Assessing rodent hippocampal involvement in the novel object recognition task. A review. Behav Brain Res 285:105–117

    Google Scholar 

  30. Pellow S, Chopin P, File SE, Briley M (1985) Validation of open: closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14:149–167

    CAS  PubMed  Google Scholar 

  31. Rickels K, Schweizer EE (1987) Current pharmacotherapy in anxiety and panic. In: Meltzer HY (ed) Psychopharmacology: the third generation of progress. Raven, New York, pp. 1193–1203

    Google Scholar 

  32. Porsolt RD (1979) Animal model of depression. Biomedicine 30:139–140

    CAS  Google Scholar 

  33. Einat H, Clenet F, Shaldubina A, Belmaker RH, Bourin M (2001) The antidepressant activity of inositol in the forced swim test involves 5-HT(2) receptors. Behav Brain Res 118:77–83

    CAS  PubMed  Google Scholar 

  34. Hinton VJ, De Vivo BC, Nereo NE (2000) Poor verbal working memory across intellectual level in boys with Duchenne dystrophy. Neurolog 54:2127–2132

    CAS  Google Scholar 

  35. Billard C, Gillet P, Barthez M-A (1998) Reading ability and processing in Duchenne muscular dystrophy and spinal muscular atrophy. Dev Med Child Neurol 40:12–20

    CAS  PubMed  Google Scholar 

  36. Roccella M, Pace R, De Gregorio MT (2003) Psychopathological assessment in children affected by Duchenne de Boulogne muscular dystrophy. Minerva Pediatr 55:267–276

    CAS  PubMed  Google Scholar 

  37. Gold PE (1986) The use of avoidance training in studies of modulation of memory storage. Behav Neural Biol 46:87–98

    CAS  PubMed  Google Scholar 

  38. Doorenweerd N, Straathof CS, Dumas EM, Spitali P, Ginjaar IB, Wokke BH, Schrans DG, van den Bergen JC et al (2014) Reduced cerebral gray matter and altered white matter in boys with Duchenne muscular dystrophy. Ann Neurol 76:403–411

    CAS  PubMed  Google Scholar 

  39. Kogelman B, Khmelinskii A, Verhaart I, Vliet LV, Bink DI, Aartsma-Rus A, Putten MV, Weerd LV (2018) Influence of full-length dystrophin on brain volumes in mouse models of Duchenne muscular dystrophy. PLoS One 13:e0194636

    PubMed  PubMed Central  Google Scholar 

  40. Aranmolate A, Tse N, Colognato H (2017) Myelination is delayed during postnatal brain development in the mdx mouse model of Duchenne muscular dystrophy. BMC Neurosci 18:63

    PubMed  PubMed Central  Google Scholar 

  41. Comim CM, Tuon L, Stertz L, Vainzof M, Kapczinski F, Quevedo J (2009) Striatum brain-derived neurotrophic factor levels are decreased in dystrophin-deficient mice. Neurosci Lett 459:66–68

    CAS  PubMed  Google Scholar 

  42. Mitre M, Mariga A, Chao MV (2017) Neurotrophin signalling: novel insights into mechanisms and pathophysiology. Clin Sci (Lond) 131:13–23

    CAS  Google Scholar 

  43. Banihani R, Smile S, Yoon G, Dupuis A, Mosleh M, Snider A (2015) Cognitive and neurobehavioral profile in boys with Duchenne muscular dystrophy. J Child Neurol 30:1472–1482

    PubMed  Google Scholar 

  44. Rose M, Sadjadi R, Weinman J (2012) Muscle Study Group: role of disease severity, illness perceptions, and mood on quality of life in muscle disease. Muscle Nerve 46:351–359

    PubMed  Google Scholar 

  45. Nuyen J, Volkers A, Verhaak P, Schellevis F, Groenewegen P, Van den Bos G (2005) Accuracy of diagnosing depression in primary care: the impact of chronic somatic and psychiatric co-morbidity. Psychol Med 35:1185–1195

    PubMed  Google Scholar 

  46. Pangalila RF, van den Bos GA, Bartels B, Bergen M, Stam HJ, Roebroeck ME (2015) Prevalence of fatigue, pain, and affective disorders in adults with Duchenne muscular dystrophy and their associations with quality of life. Arch Phys Med Rehabil 96:1242–1247

    PubMed  Google Scholar 

  47. Grounds MD, Torrisi J (2004) Anti-TNFalpha (Remicade) therapy protects dystrophic skeletal muscle from necrosis. FASEB J 18:676–682

    CAS  Google Scholar 

  48. Vellosa JCR, Parabocz GC, Manente FA, Ribas JT, Lima LW (2013) Alterações metabólicas e inflamatórias em condições de estresse oxidativo. Rev Ciênc Fram Básica Apl 34:304–312

    Google Scholar 

  49. Alder J, Kanki H, Valtorta F, Greengard P, Poo MM (1995) Overexpression of synaptophysin enhances neurotransmitter secretion at Xenopus neuromuscular synapses. J Neurosci 15:511–519

    CAS  PubMed  Google Scholar 

  50. Lewerenz J, Maher P (2015) Chronic glutamate toxicity in neurodegenerative diseases—what is the evidence? Front Neurosci 9:469

    PubMed  PubMed Central  Google Scholar 

  51. Allen DG, Gervasio OL, Yeung EW, Whitehead NP (2010) Calcium and the damage pathways in muscular dystrophy. Can J Physiol Pharmacol 88:83–91

    CAS  PubMed  Google Scholar 

  52. van Westering TL, Betts CA, Wood MJ (2015) Current understanding of molecular pathology and treatment of cardiomyopathy in Duchenne muscular dystrophy. Molecules 20:8823–8855

    PubMed  PubMed Central  Google Scholar 

  53. Schubert D, Piasecki D (2001) Oxidative glutamate toxicity can be a component of the excitotoxicity cascade. J Neurosci 21:7455–7462

    CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This research was financially supported by grants from CNPq and UNISUL. MIR and MV are CNPq Research Fellows.

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Authors and Affiliations

  1. Research Group on Neurodevelopment of Childhood and Adolescence, Laboratory of Experimental Neuroscience, Postgraduate Program in Health Sciences, University of South Santa Catarina, Palhoça, SC, Brazil

    Clarissa M. Comim, Letícia Ventura, Viviane Freiberger, Paula Dias, Daiane Bragagnolo, Matheus L. Dutra & Ricardo A. Amaral

  2. Laboratory of Epidemiology, Postgraduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, SC, 88806-000, Brazil

    Ana Lucia S. Camargo-Fagundes & Maria I. Rosa

  3. Laboratory of Immunopharmacology, Instituto Oswaldo Cruz/IOC/FIOCRUZ-Manguinhos, Rio de Janeiro, Brazil

    Patrícia A. Reis & Hugo C. Castro-Faria-Neto

  4. Human Genome Research Center, Biosciences Institute, University of São Paulo, São Paulo, SP, Brazil

    Mariz Vainzof

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  1. Clarissa M. Comim
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  2. Letícia Ventura
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Corresponding author

Correspondence to Clarissa M. Comim.

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All experimental procedures involving animals were performed in accordance with the NIH Guide for the Care and Use of Laboratory Animals. All protocols performed were approved by the ethics committee at UNISUL (protocol number 16.033.4.01.IV).

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Comim, C.M., Ventura, L., Freiberger, V. et al. Neurocognitive Impairment in mdx Mice. Mol Neurobiol 56, 7608–7616 (2019). https://doi.org/10.1007/s12035-019-1573-7

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