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Animal Models of Dementia pp 485–492Cite as

Cognitive Dysfunction in Genetic Mouse Models of Parkinsonism

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Part of the book series: Neuromethods ((NM,volume 48))

Abstract

Parkinson’s disease (PD) is primarily recognized as a motor disorder; however, patients also present with a wide range of nonmotor manifestations. Cognitive dysfunctions in nondemented PD patients can occur early in the disease and primarily consist of deficits in executive function. Because it can be assessed with noninvasive measurement tools, cognitive dysfunction could be evaluated to determine the effects of potential disease-modifying agents in patients. A challenge is to reproduce these deficits in animals for preclinical drug testing. Genetic mouse models of PD have been generated based on mutations causing rare familial forms of PD. Although only a few models show extensive nigrostriatal dopamine cell loss, several present extensive anomalies in functions that are also altered in premanifest phases of PD. Here we review the few studies that have so far investigated cognitive function in these new models.

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References

  1. Knowlton BJ, Mangels JA, Squire LR (1996) A neostriatal habit learning system in humans. Science 273:1399–1402.

    Article  PubMed  CAS  Google Scholar 

  2. Levin BE, Katzen HL (2005) Early cognitive changes and nondementing behavioral abnormalities in Parkinson’s disease. Adv Neurol 96:84–94.

    PubMed  Google Scholar 

  3. Aarsland D, Tandberg E, Larsen JP, Cummings JL (1996) Frequency of dementia in Parkinson disease. Arch Neurol 53:538–542.

    Article  PubMed  CAS  Google Scholar 

  4. Aarsland D, Zaccai J, Brayne C (2005) A systematic review of prevalence studies of dementia in Parkinson’s disease. Mov Disord 20:1255–1263.

    Article  PubMed  Google Scholar 

  5. Javin CC, Aarsland D, Larsen JP (2005) Cognitive predictors of dementia in Parkinson’s disease: a community-based, 4 longitudinal study. J Geriat Psychiatry Neurol 18:149–154.

    Article  Google Scholar 

  6. Taylor AE, Saint-Cyr JA, Lang AE (1986) Frontal lobe dysfunction in Parkinson’s disease. The cortical focus of neostriatal outflow. Brain 109:845–883.

    Article  PubMed  Google Scholar 

  7. Canavan AG, Passingham RE, Marsden CD, Quinn N, Wyke M, Polkey CE (1989) The performance on learning tasks of patients in the early stages of Parkinson’s disease. Neuropsychologia 27:141–156.

    Article  PubMed  CAS  Google Scholar 

  8. Downes JJ, Roberts AC, Sahakian BJ, Evenden JL, Morris RG, Robbins TW (1989) Impaired extra-dimensional shift performance in medicated and unmedicated Parkinson’s disease: evidence for a specific attentional dysfunction. Neuropsychologia 27:1329–1343.

    Article  PubMed  CAS  Google Scholar 

  9. Owen AM, James M, Leigh PN, et al. (1992) Fronto-striatal cognitive deficits at different stages of Parkinson’s disease. Brain 115:1727–1751.

    Article  PubMed  Google Scholar 

  10. Packard MG, McGaugh JL (1996) Inactivation of hippocampus or caudate nucleus with lidocaine differentially affects expression of place and response learning. Neurobiol Learn Mem 65:65–72.

    Article  PubMed  CAS  Google Scholar 

  11. Ragozzino ME, Wilcox C, Raso M, Kesner RP (1999) Involvement of rodent prefrontal cortex subregions in strategy switching. Behav Neurosci 113:32–41.

    Article  PubMed  CAS  Google Scholar 

  12. Cole BJ, Robbins TW (1992) Forebrain norepinephrine: role in controlled information processing in the rat. Neuropsychopharmacology 7:129–142.

    PubMed  CAS  Google Scholar 

  13. Cools R, Barker RA, Sahakian BJ, Robbins TW (2001) Enhanced or impaired cognitive function in Parkinson’s disease as a function of dopaminergic medication and task demands. Cereb Cortex 11:1136–1143.

    Article  PubMed  CAS  Google Scholar 

  14. Swainson R, Rogers RD, Sahakian BJ, Summers BA, Polkey CE, Robbins TW (2000) Probabilistic learning and reversal deficits in patients with Parkinson’s disease or frontal or temporal lobe lesions: possible adverse effects of dopaminergic medication. Neuropsy­chologia 38:596–612.

    Article  PubMed  CAS  Google Scholar 

  15. Gotham AM, Brown RG, Marsden CD (1988) ‘Frontal’ cognitive function in patients with Parkinson’s disease ‘on’ and ‘off’ levodopa. Brain 111:299–321.

    Article  PubMed  Google Scholar 

  16. Mehta MA, Manes FF, Magnolfi G, Sahakian BJ, Robbins TW (2004) Impaired set-shifting and dissociable effects on tests of spatial working memory following the dopamine D2 receptor antagonist sulpiride in human volunteers. Psychopharmacology (Berl) 176:331–342.

    Article  CAS  Google Scholar 

  17. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211.

    Article  PubMed  Google Scholar 

  18. Taylor JR, Elsworth JD, Roth RH, Sladek JR Jr, Redmond DE Jr (1990) Cognitive and motor deficits in the acquisition of an object retrieval/detour task in MPTP-treated monkeys. Brain 113:617–637.

    Article  PubMed  Google Scholar 

  19. Schneider JS, Kovelowski CJ 2nd (1990) Chronic exposure to low doses of MPTP. I. Cognitive deficits in motor asymptomatic monkeys. Brain Res 519:122–128.

    CAS  Google Scholar 

  20. Schneider JS, Pope-Coleman A (1995) Cognitive deficits precede motor deficits in a slowly progressing model of parkinsonism in the monkey. Neurodegeneration 4:245–255.

    Article  PubMed  CAS  Google Scholar 

  21. Slovin H, Abeles M, Vaadia E, Haalman I, Prut Y, Bergman H (1999) Frontal cognitive impairments and saccadic deficits in low-dose MPTP-treated monkeys. J Neurophysiol 81:858–874.

    PubMed  CAS  Google Scholar 

  22. Tanila H, Björklund M, Riekkinen P Jr (1998) Cognitive changes in mice following moderate MPTP exposure. Brain Res Bull 45:577–582.

    Article  PubMed  CAS  Google Scholar 

  23. Dluzen DE, Kreutzberg JD (1993) 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) disrupts social memory/recognition processes in the male mouse. Brain Res 609:98–102.

    Article  PubMed  CAS  Google Scholar 

  24. De Leonibus E, Pascucci T, Lopez S, Oliverio A, Amalric M, Mele A (2007) Spatial deficits in a mouse model of Parkinson disease. Psychopharmacology (Berl) 194:517–525.

    Article  Google Scholar 

  25. Sonnier L, Le Pen G, Hartmann A, et al. (2007) Progressive loss of dopaminergic neurons in the ventral midbrain of adult mice heterozygote for Engrailed1. J Neurosci 27:1063–1071.

    Article  PubMed  CAS  Google Scholar 

  26. Nunes I, Tovmasian LT, Silva RM, Burke RE, Goff SP (2003) Pitx3 is required for development of substantia nigra dopaminergic neurons. Proc Natl Acad Sci U S A 100:4245–4250.

    Article  PubMed  CAS  Google Scholar 

  27. Zetterström RH, Solomin L, Jansson L, Hoffer BJ, Olson L, Perlmann T (1997) Dopamine neuron agenesis in Nurr1-deficient mice. Science 276:248–250.

    Article  PubMed  Google Scholar 

  28. Hwang DY, Fleming SM, Ardayfio P, et al. (2005) 3,4-dihydroxyphenylalanine reverses the motor deficits in Pitx3-deficient aphakia mice: behavioral characterization of a novel genetic model of Parkinson’s disease. J Neurosci 25:2132–2137.

    Article  PubMed  CAS  Google Scholar 

  29. Eells JB, Lipska BK, Yeung SK, Misler JA, Nikodem VM (2002) Nurr1-null heterozygous mice have reduced mesolimbic and mesocortical dopamine levels and increased stress-induced locomotor activity. Behav Brain Res 136:267–275.

    Article  PubMed  CAS  Google Scholar 

  30. Fleming SM, Fernagut PO, Chesselet MF (2005) Genetic mouse models of parkinsonism: strengths and limitations. NeuroRx 2:495–503.

    Article  PubMed  Google Scholar 

  31. Manning-Bog AB, Langston JW (2007) Model fusion, the next phase in developing animal models for Parkinson’s disease. Neurotox Res 11:219–240.

    Article  PubMed  CAS  Google Scholar 

  32. Polymeropoulos MH, Lavedan C, Leroy E, et al. (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047.

    Article  PubMed  CAS  Google Scholar 

  33. Kruger R, Kuhn W, Muller T, et al. (1998) Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet 18:106–108.

    Article  PubMed  CAS  Google Scholar 

  34. Singleton AB, Farrer M, Johnson J, et al. (2003) Alpha-Synuclein locus triplication causes Parkinson’s disease. Science 302:841.

    Article  PubMed  CAS  Google Scholar 

  35. Chartier-Harlin MC, Kachergus J, Roumier C, et al. (2004) Alpha-synuclein locus duplication as a cause of familial Parkinson’s disease. Lancet 364:1167–1169

    Article  PubMed  CAS  Google Scholar 

  36. Spillantini MG, Schmidt ML, Lee VM, et al. (1997) Alpha-synuclein in Lewy bodies. Nature 388: 839–840.

    Article  PubMed  CAS  Google Scholar 

  37. Neumann M, Kahle PJ, Giasson BI, et al. (2002) Misfolded proteinase K-resistant hyperphosphorylated alpha-synuclein in aged transgenic mice with locomotor deterioration and in human alpha-synucleinopathies. J Clin Invest 110:1429–1439.

    PubMed  CAS  Google Scholar 

  38. Freichel C, Neumann M, Ballard T, et al. (2007) Age-dependent cognitive decline and amygdala pathology in alpha-synuclein transgenic mice. Neurobiol Aging 28:1421–1435.

    Article  PubMed  CAS  Google Scholar 

  39. Nuber S, Petrasch-Parwez E, Winner B, et al. (2008) Neurodegeneration and motor dysfunction in a conditional model of Parkinson’s disease. J Neurosci 28:2471–2484.

    Article  PubMed  CAS  Google Scholar 

  40. Rockenstein E, Mallory M, Hashimoto M, et al. (2002) Differential neuropathological alterations in transgenic mice expressing alpha-synuclein from the platelet-derived growth factor and Thy-1 promoters. J Neurosci Res 68:568–578.

    Article  PubMed  CAS  Google Scholar 

  41. Fernagut PO, Hutson CB, Fleming SM, et al. (2007) Behavioral and histopathological consequences of paraquat intoxication in mice: effects of alpha-synuclein overexpression. Synapse 61, 991–1001.

    Article  PubMed  CAS  Google Scholar 

  42. Hean, S, Richter, F, Torres, ES, et al. (2010) Mice overexpressing human alpha synuclein (thy1-aSyn) show dopamine loss, catalepsy and sever motor deficits partially rescued by L-DOPA at 14 months of age. Neurosci Abst 36.

    Google Scholar 

  43. Fleming SM, Salcedo J, Hutson CB, et al. (2006) Behavioral effects of dopaminergic agonists in transgenic mice overexpressing human wildtype alpha-synuclein. Neuroscience 142:1245–1253.

    Article  PubMed  CAS  Google Scholar 

  44. Wu N, Cepeda C, Masliah E, et al. (2005) Abnormal glutamate and dopamine receptor function in the striatum of α-synuclein-overexpressing mice. Program No. 85.12. AbstractViewer/Itinerary Planner. Wasington, DC: Society for Neuroscience

    Google Scholar 

  45. Wang L, Fleming SM, Chesselet M-F, Taché Y (2008) Abnormal colonic motility in mice overexpressing human wild-type α-synuclein. Neuroreport 19:873–876.

    Article  PubMed  CAS  Google Scholar 

  46. Fleming SM, Jordan, MC, Masliah E, et al. (2007) Alterations in baroreceptor function in transgenic mice overexpressing human wildtype alpha synuclein. Program No. 50.9. Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience.

    Google Scholar 

  47. Fleming SM, Tetreault NA, Mulligan CM, et al. (2008) Alterations in olfactory function in transgenic mice overexpressing human wild-type alpha synuclein. Eur J Neurosci 28:247–256.

    Article  PubMed  Google Scholar 

  48. Aston-Jones G, Rajkowski J, Cohen J (1999) Role of locus coeruleus in attention and behavioral flexibility. Biol Psychiatry 46:1309–1320.

    Article  PubMed  CAS  Google Scholar 

  49. Seu E, Lang A, Rivera RJ, Jentsch JD (2009) Inhibition of the norepinephrine transporter improves behavioral flexibility in rats and monkeys. Psychopharmacology 202:505–519.

    Article  PubMed  CAS  Google Scholar 

  50. Fleming SM, Garcia EC, Masliah E, et al. (2008) Impaired reversal learning in transgenic mice overexpressing human wildtype alpha-synuclein. Neuroscience Meeting Planner. Washington DC: Society for Neuroscience.

    Google Scholar 

  51. Goldberg MS, Fleming SM, Palacino JJ, et al. (2003) Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. Journal of Biological Chemistry 278: 43628–43635.

    Article  PubMed  CAS  Google Scholar 

  52. Von Coelln R, Thomas B, Savitt JM, et al. (2004) Loss of locus coeruleus neurons and reduced startle in parkin null mice. Proc Natl Acad Sci U S A 101:10744–10949.

    Article  PubMed  CAS  Google Scholar 

  53. Zhu XR, Maskri L, Herold C, et al. (2007) Non-motor behavioural impairments in parkin-deficient mice. Eur J Neurosci 26:1902–1911.

    Article  PubMed  Google Scholar 

  54. Itier JM, Ibanez P, Mena MA, et al. (2003) Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse. Hum Mol Genet 12:2277–2291.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We gratefully acknowledge the valuable assistance of Eddie C. Garcia. Funded by Morris K. Udall Parkinson’s Disease Research Center of Excellence at UCLA (P50NS38367), the American Parkinson Disease Association, and the American Parkinson Disease Association UCLA Center of Excellence.

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Authors and Affiliations

  1. Department of Neurology, The David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Sheila M. Fleming & Marie-FranÇoise Chesselet

  2. Department of Psychology, The David Geffen School of Medicine at UCLA, CA, 90095-1769, Los Angeles

    J. David Jentsch

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  1. Sheila M. Fleming
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  2. J. David Jentsch
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  3. Marie-FranÇoise Chesselet
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Editors and Affiliations

  1. Institute Born-Bunge, Lab of Neurochemistry & Behaviour, University of Antwerp, Universiteitsplein 1, Wilrijk, 2610, Belgium

    Peter Paul De Deyn

  2. Institute Born-Bunge, Lab of Neurochemistry & Behaviour, University of Antwerp, Universiteitsplein 1, Wilrijk, 2610, Belgium

    Debby Van Dam

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Fleming, S.M., Jentsch, J.D., Chesselet, MF. (2011). Cognitive Dysfunction in Genetic Mouse Models of Parkinsonism. In: De Deyn, P., Van Dam, D. (eds) Animal Models of Dementia. Neuromethods, vol 48. Humana Press. https://doi.org/10.1007/978-1-60761-898-0_25

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  • DOI: https://doi.org/10.1007/978-1-60761-898-0_25

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