Skip to main content
SpringerLink
Log in

Transgenic Rodent Models to Study Alpha-Synuclein Pathogenesis, with a Focus on Cognitive Deficits

  • Chapter
  • First Online:
Behavioral Neurobiology of Huntington's Disease and Parkinson's Disease

Part of the book series: Current Topics in Behavioral Neurosciences ((CTBN,volume 22))

Abstract

The aggregation of alpha-synuclein (aSyn) has been implicated in a number of degenerative diseases collectively termed synucleinopathies. Although most cases of synucleinopathies are idiopathic in nature, there are familial cases of these diseases that are due to mutations or multiplications of the gene coding for aSyn. Two of the most common synucleinopathies are Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Both of these diseases present with cognitive deficits, though with different clinical and temporal features. In PD, cognitive deficits are subtle, may occur before the onset of the classical motor symptoms, and only occasionally lead to dementia in the later stages of the disease. In contrast, dementia is the dominating feature of DLB from the disease onset. The impact of aSyn pathology on the development of neurobiological and behavioral impairments can be investigated using rodent models. There are currently several lines of transgenic mice overexpressing wild-type or mutated aSyn under various promoters. This review will provide an updated synopsis of the mouse lines available, summarize their cognitive deficits, and reflect on how deficits observed in these mice relate to the disease process in humans. In addition, we will review mouse lines where knockout strategies have been applied to study the effects of aSyn on various cognitive tasks and comment on how these lines have been used in combination with other transgenic strains, or with human aSyn overexpression by viral vectors. Finally, we will discuss the recent advent of bacterial artificial chromosome (BAC) transgenic models of PD and their effectiveness in modeling cognitive decline in PD.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Aarsland D, Kurz MW (2010) The epidemiology of dementia associated with parkinson’s disease. Brain Pathol 20:633–639

    Article  PubMed  Google Scholar 

  • Abeliovich A, Schmitz Y, Fariñas I, Choi-Lundberg D, Ho W-H, Castillo PE, Shinsky N, Verdugo JMG, Armanini M, Ryan A, Hynes M, Phillips H, Sulzer D, Rosenthal A (2000) Mice lacking α-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25:239–252

    Article  CAS  PubMed  Google Scholar 

  • Amschl D, Neddens J, Havas D, Flunkert S, Rabl R, Romer H, Rockenstein E, Masliah E, Windisch M, Hutter-Paier B (2013) Time course and progression of wild type alpha-Synuclein accumulation in a transgenic mouse model. BMC Neuroscience 14:6

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Beach T, Adler C, Lue L, Sue L, Bachalakuri J, Henry-Watson J, Sasse J, Boyer S, Shirohi S, Brooks R, Eschbacher J, White C III, Akiyama H, Caviness J, Shill H, Connor D, Sabbagh M, Walker D (2009) Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction. Acta Neuropathol 117:613–634

    Article  PubMed Central  PubMed  Google Scholar 

  • Botton PH, Costa MS, Ardais AP, Mioranzza S, Souza DO, da Rocha JBT, Porciúncula LO (2010) Caffeine prevents disruption of memory consolidation in the inhibitory avoidance and novel object recognition tasks by scopolamine in adult mice. Behav Brain Res 214:254–259

    Article  CAS  PubMed  Google Scholar 

  • Braak H, Del Tredici K, Bratzke H, Hamm-Clement J, Sandmann-Keil D, Rüb U (2002) Staging of the intracerebral inclusion body pathology associated with idiopathic Parkinson’s disease (preclinical and clinical stages). J Neurol 249:1–5

    Article  Google Scholar 

  • Braak H, Tredici KD, Rüb U, de Vos RAI, Jansen Steur ENH, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211

    Article  PubMed  Google Scholar 

  • Braak H, Rüb U, Del Tredici K (2006) Cognitive decline correlates with neuropathological stage in Parkinson’s disease. J Neurol Sci 248:255–258

    Article  PubMed  Google Scholar 

  • Brown RG, Lacomblez L, Landwehrmeyer BG, Bak T, Uttner I, Dubois B, Agid Y, Ludolph A, Bensimon G, Payan C, Leigh NP, N. S. G. (2010) Cognitive impairment in patients with multiple system atrophy and progressive supranuclear palsy. Brain 133:2382–2393

    Article  PubMed  Google Scholar 

  • Chen PE, Specht CG, Morris RGM, Schoepfer R (2002) Spatial learning is unimpaired in mice containing a deletion of the alpha-synuclein locus. Eur J Neurosci 16:154–158

    Article  PubMed  Google Scholar 

  • Chesselet M-F, Richter F (2011) Modelling of Parkinson’s disease in mice. Lancet Neurol 10:1108–1118

    Article  PubMed  Google Scholar 

  • Clinton LK, Blurton-Jones M, Myczek K, Trojanowski JQ, LaFerla FM (2010) Synergistic Interactions between Aβ, Tau, and α-Synuclein: Acceleration of Neuropathology and Cognitive Decline. J Neurosci 30:7281–7289

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Dickson DW, Braak H, Duda JE, Duyckaerts C, Gasser T, Halliday GM, Hardy J, Leverenz JB, Del Tredici K, Wszolek ZK, Litvan I (2009) Neuropathological assessment of Parkinson’s disease: refining the diagnostic criteria. Lancet Neurol 8:1150–1157

    Article  CAS  PubMed  Google Scholar 

  • Farrer M, Kachergus J, Forno L, Lincoln S, Wang D-S, Hulihan M, Maraganore D, Gwinn-Hardy K, Wszolek Z, Dickson D, Langston JW (2004) Comparison of kindreds with parkinsonism and α-synuclein genomic multiplications. Ann Neurol 55:174–179

    Article  CAS  PubMed  Google Scholar 

  • Fernagut PO, Tison F (2012) Animal models of multiple system atrophy. Neuroscience 211:77–82

    Article  CAS  PubMed  Google Scholar 

  • Freichel C, Neumann M, Ballard T, Müller V, Woolley M, Ozmen L, Borroni E, Kretzschmar HA, Haass C, Spooren W, Kahle PJ (2007) Age-dependent cognitive decline and amygdala pathology in α-synuclein transgenic mice. Neurobiol Aging 28:1421–1435

    Article  CAS  PubMed  Google Scholar 

  • Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg MS, Shen J, Takio K, Iwatsubo T (2002) alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 4:160–164

    Article  CAS  PubMed  Google Scholar 

  • Gardai SJ, Mao W, Schüle B, Babcock M, Schoebel S, Lorenzana C, Alexander J, Kim S, Glick H, Hilton K, Fitzgerald JK, Buttini M, Chiou S-S, McConlogue L, Anderson JP, Schenk DB, Bard F, Langston JW, Yednock T, Johnston JA (2013) Elevated Alpha-Synuclein Impairs Innate Immune Cell Function and Provides a Potential Peripheral Biomarker for Parkinson’s Disease. PLoS ONE 8:e71634

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Geser F, Wenning GK, Poewe W, McKeith I (2005) How to diagnose dementia with Lewy bodies: State of the art. Mov Disord 20:S11–S20

    Article  PubMed  Google Scholar 

  • Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, Lee VMY (2002) Neuronal α-synucleinopathy with severe movement disorder in mice expressing A53T Human α-Synuclein. Neuron 34:521–533

    Article  CAS  PubMed  Google Scholar 

  • Gurvich C, Georgiou-Karistianis N, Fitzgerald PB, Millist L, White OB (2007) Inhibitory control and spatial working memory in Parkinson’s disease. Mov Disord 22:1444–1450

    Article  PubMed  Google Scholar 

  • Hall H, Jewett M, Landeck N, Nilsson N, Schagerlöf U, Leanza G, Kirik D (2013) Characterization of cognitive deficits in rats overexpressing human alpha-synuclein in the ventral tegmental area and medial septum using recombinant adeno-associated viral vectors. PLoS ONE 8:e64844

    Article  PubMed Central  PubMed  Google Scholar 

  • Halliday G, Holton J, Revesz T, Dickson D (2011) Neuropathology underlying clinical variability in patients with synucleinopathies. Acta Neuropathol 122:187–204

    Article  CAS  PubMed  Google Scholar 

  • Hansen L, Salmon D, Galasko D, Masliah E, Katzman R, DeTeresa R, Thal L, Pay MM, Hofstetter R, Klauber M, Rice V, Butters N, Alford M (1990) The Lewy body variant of Alzheimer’s disease: a clinical and pathologic entity. Neurology 40:1

    Article  CAS  PubMed  Google Scholar 

  • Hansen C, Björklund T, Petit GH, Lundblad M, Murmu RP, Brundin P, Li J-Y (2013) A novel α-synuclein-GFP mouse model displays progressive motor impairment, olfactory dysfunction and accumulation of α-synuclein-GFP. Neurobiology of Disease. 56:145–155

    Article  CAS  PubMed  Google Scholar 

  • Hashimoto M, Rockenstein E, Masliah E (2003) Transgenic models of α-synuclein pathology. Ann NY Acad Sci 991:171–188

    Article  CAS  PubMed  Google Scholar 

  • Ikeuchi T, Kakita A, Shiga A, Kasuga K, Kaneko H, Tan C, Idezuka J, Wakabayashi K, Onodera O, Iwatsubo T, Nishizawa M, Takahashi H, Ishikawa A (2008) Patients homozygous and heterozygous for SNCA duplication in a family with parkinsonism and dementia. Arch Neurol 65:514–519

    Article  PubMed  Google Scholar 

  • Janezic S, Threlfell S, Dodson PD, Dowie MJ, Taylor TN, Potgieter D, Parkkinen L, Senior SL, Anwar S, Ryan B, Deltheil T, Kosillo P, Cioroch M, Wagner K, Ansorge O, Bannerman DM, Bolam JP, Magill PJ, Cragg SJ, Wade-Martins R (2013) Deficits in dopaminergic transmission precede neuron loss and dysfunction in a new Parkinson model. Proc Natl Acad Sci 110:E4016–E4025

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Janvin CC, Larsen JP, Aarsland D, Hugdahl K (2006) Subtypes of mild cognitive impairment in parkinson’s disease: Progression to dementia. Mov Disord 21:1343–1349

    Article  PubMed  Google Scholar 

  • Kahle PJ (2008) alpha-Synucleinopathy models and human neuropathology: similarities and differences. Acta Neuropathol 115:87–95

    Article  CAS  PubMed  Google Scholar 

  • Kahle PJ, Neumann M, Ozmen L, Müller V, Jacobsen H, Schindzielorz A, Okochi M, Leimer U, van der Putten H, Probst A, Kremmer E, Kretzschmar HA, Haass C (2000) Subcellular Localization of Wild-Type and Parkinson’s Disease-Associated Mutant α-Synuclein in Human and Transgenic Mouse Brain. J Neurosci 20:6365–6373

    CAS  PubMed  Google Scholar 

  • Kao AW, Racine CA, Quitania LC, Kramer JH, Christine CW, Miller BL (2009) Cognitive and neuropsychiatric profile of the synucleinopathies: Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. Alzheimer Dis Assoc Disord 23(365–370):3. doi:10.1097/WAD.1090b1013e3181b5065d

    Google Scholar 

  • Kéri S, Nagy H, Myers CE, Benedek G, Shohamy D, Gluck MA (2008) Risk and protective haplotypes of the alpha-synuclein gene associated with Parkinson’s disease differentially affect cognitive sequence learning. Genes Brain Behav 7:31–36

    PubMed  Google Scholar 

  • Kéri S, Moustafa AA, Myers CE, Benedek G, Gluck MA (2010) α-Synuclein gene duplication impairs reward learning. Proc Natl Acad Sci 107:15992–15994

    Article  PubMed Central  PubMed  Google Scholar 

  • Kirik D, Rosenblad C, Burger C, Lundberg C, Johansen TE, Muzyczka N, Mandel RJ, Björklund A (2002) Parkinson-Like Neurodegeneration Induced by Targeted Overexpression of α-Synuclein in the Nigrostriatal System. J Neurosci 22:2780–2791

    CAS  PubMed  Google Scholar 

  • Klein RL, King MA, Hamby ME, Meyer EM (2002) Dopaminergic cell loss induced by human A30P a-synuclein gene transfer to the rat substantia nigra. Hum Gene Ther 13:605–612

    Article  CAS  PubMed  Google Scholar 

  • Kokhan VS, Afanasyeva MA, Van’kin GI (2012) α-Synuclein knockout mice have cognitive impairments. Behav Brain Res 231:226–230

    Article  CAS  PubMed  Google Scholar 

  • Krüger R, Kuhn W, Leenders KL, Sprengelmeyer R, Müller T, Woitalla D, Portman AT, Maguire RP, Veenma L, Schröder U, Schöls L, Epplen JT, Riess O, Przuntek H (2001) Familial parkinsonism with synuclein pathology: clinical and PET studies of A30P mutation carriers. Neurology 56:1355–1362

    Article  PubMed  Google Scholar 

  • Kuo Y-M, Li Z, Jiao Y, Gaborit N, Pani AK, Orrison BM, Bruneau BG, Giasson BI, Smeyne RJ, Gershon MD, Nussbaum RL (2010) Extensive enteric nervous system abnormalities in mice transgenic for artificial chromosomes containing Parkinson disease-associated Π± -synuclein gene mutations precede central nervous system changes. Hum Mol Genet 19:1633–1650

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lam HA, Wu N, Cely I, Kelly RL, Hean S, Richter F, Magen I, Cepeda C, Ackerson LC, Walwyn W, Masliah E, Chesselet M-F, Levine MS, Maidment NT (2011) Elevated tonic extracellular dopamine concentration and altered dopamine modulation of synaptic activity precede dopamine loss in the striatum of mice overexpressing human α-synuclein. J Neurosci Res 89:1091–1102

    Article  CAS  PubMed  Google Scholar 

  • Li B, Arime Y, Hall FS, Uhl GR, Sora I (2010) Impaired spatial working memory and decreased frontal cortex BDNF protein level in dopamine transporter knockout mice. Eur J Pharmacol 628:104–107

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lim Y, Kehm VM, Lee EB, Soper JH, Li C, Trojanowski JQ, Lee VMY (2011) α-syn suppression reverses synaptic and memory defects in a mouse model of dementia with lewy bodies. J Neurosci 31:10076–10087

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lin X, Parisiadou L, Sgobio C, Liu G, Yu J, Sun L, Shim H, Gu X-L, Luo J, Long C-X, Ding J, Mateo Y, Sullivan PH, Wu L-G, Goldstein DS, Lovinger D, Cai H (2012) Conditional expression of parkinson’s disease-related mutant α-synuclein in the midbrain dopaminergic neurons causes progressive neurodegeneration and degradation of transcription factor nuclear receptor related 1. J Neurosci 32:9248–9264

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lo Bianco C, Ridet JL, Schneider BL, Déglon N, Aebischer P (2002) α-Synucleinopathy and selective dopaminergic neuron loss in a rat lentiviral-based model of Parkinson’s disease. Proc Natl Acad Sci 99:10813–10818

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Magen I, Chesselet M-F (2010) Genetic mouse models of Parkinson’s disease: the state of the art. Prog Brain Res 184:53–87 (Elsevier, Chapter 4)

    Google Scholar 

  • Magen I, Chesselet M-F (2011) Mouse models of cognitive deficits due to alpha-synuclein pathology. J Parkinson’s Dis 1:217–227

    CAS  Google Scholar 

  • Magen I, Fleming SM, Zhu C, Garcia EC, Cardiff KM, Dinh D, De La Rosa K, Sanchez M, Torres ER, Masliah E, David Jentsch J, Chesselet M-F (2012) Cognitive deficits in a mouse model of pre-manifest Parkinson’s disease. Eur J Neurosci 35:870–882

    Article  PubMed Central  PubMed  Google Scholar 

  • Maingay M, Romero-Ramos M, Carta M, Kirik D (2006) Ventral tegmental area dopamine neurons are resistant to human mutant alpha-synuclein overexpression. Neurobiol Dis 23:522–532

    Article  CAS  PubMed  Google Scholar 

  • Martin LJ, Semenkow S, Hanaford A, Wong M (2014) The mitochondrial permeability transition pore regulates Parkinson’s disease development in mutant α-synuclein transgenic mice. Neurobiol Aging 35:1132–1152

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A, Sagara Y, Sisk A, Mucke L (2000) Dopaminergic loss and inclusion body formation in α-synuclein mice: implications for neurodegenerative disorders. Science 287:1265–1269

    Article  CAS  PubMed  Google Scholar 

  • Masliah E, Rockenstein E, Veinbergs I, Sagara Y, Mallory M, Hashimoto M, Mucke L (2001) β-Amyloid peptides enhance α-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer’s disease and Parkinson’s disease. Proc Natl Acad Sci 98:12245–12250

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Masliah E, Rockenstein E, Mante M, Crews L, Spencer B, Adame A, Patrick C, Trejo M, Ubhi K, Rohn TT, Mueller-Steiner S, Seubert P, Barbour R, McConlogue L, Buttini M, Games D, Schenk D (2011) Passive immunization reduces behavioral and neuropathological deficits in an alpha-synuclein transgenic model of Lewy Body Disease. PLoS ONE 6:e19338

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • McKeith IG, Dickson DW, Lowe J, Emre M, O’Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M, DLB co. (2005) Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65:1863–1872

    Article  CAS  PubMed  Google Scholar 

  • Morra LF, Donovick PJ (2013) Clinical presentation and differential diagnosis of dementia with Lewy bodies: a review. Int J Geriatr Psychiatry n/a-n/a

    Google Scholar 

  • Neumann M, Kahle PJ, Giasson BI, Ozmen L, Borroni E, Spooren W, Müller V, Odoy S, Fujiwara H, Hasegawa M, Iwatsubo T, Trojanowski JQ, Kretzschmar HA, Haass C (2002) Misfolded proteinase K-resistant hyperphosphorylated α-synuclein in aged transgenic mice with locomotor deterioration and in human α-synucleinopathies. J Clin Investig 110:1429–1439

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Nuber S, Petrasch-Parwez E, Winner B, Winkler J, von Hörsten S, Schmidt T, Boy J, Kuhn M, Nguyen HP, Teismann P, Schulz JB, Neumann M, Pichler BJ, Reischl G, Holzmann C, Schmitt I, Bornemann A, Kuhn W, Zimmermann F, Servadio A, Riess O (2008) Neurodegeneration and motor dysfunction in a conditional model of parkinson’s disease. J Neurosci 28:2471–2484

    Article  CAS  PubMed  Google Scholar 

  • Oaks AW, Frankfurt M, Finkelstein DI, Sidhu A (2013) Age-dependent effects of A53T alpha-synuclein on behavior and dopaminergic function. PLoS ONE 8:e60378

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39:409–421

    Article  CAS  PubMed  Google Scholar 

  • Pagonabarraga J, Kulisevsky J (2012) Cognitive impairment and dementia in Parkinson’s disease. Neurobiol Dis 46:590–596

    Article  PubMed  Google Scholar 

  • Paumier KL, Sukoff Rizzo SJ, Berger Z, Chen Y, Gonzales C, Kaftan E, Li L, Lotarski S, Monaghan M, Shen W, Stolyar P, Vasilyev D, Zaleska M, Hirst WD, Dunlop J (2013) Behavioral Characterization of A53T Mice Reveals Early and Late Stage Deficits Related to Parkinson’s Disease. PLoS ONE 8:e70274

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Peña-Oliver Y, Buchman VL, Dalley JW, Robbins TW, Schumann G, Ripley TL, King SL, Stephens DN (2011) Deletion of alpha-synuclein decreases impulsivity in mice. Genes Brain Behav 11:137–146

    Article  PubMed Central  PubMed  Google Scholar 

  • Peterson DA, Elliott C, Song DD, Makeig S, Sejnowski TJ, Poizner H (2009) Probabilistic reversal learning is impaired in Parkinson’s disease. Neuroscience 163:1092–1101

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Pfeiffer HCV, Løkkegaard A, Zoetmulder M, Friberg L, Werdelin L (2013) Cognitive impairment in early-stage non-demented Parkinson’s disease patients. Acta Neurologica Scandinavica

    Google Scholar 

  • Price DL, Rockenstein E, Ubhi K, Phung V, MacLean-Lewis N, Askay D, Cartier A, Spencer B, Patrick C, Desplats P, Ellisman MH, Masliah E (2010) Alterations in mGluR5 expression and signaling in Lewy Body disease and in transgenic models of alpha-synucleinopathy—implications for excitotoxicity. PLoS ONE 5:e14020

    Article  PubMed Central  PubMed  Google Scholar 

  • Puschmann A, Ross OA, Vilariño-Güell C, Lincoln SJ, Kachergus JM, Cobb SA, Lindquist SG, Nielsen JE, Wszolek ZK, Farrer M, Widner H, van Westen D, Hägerström D, Markopoulou K, Chase BA, Nilsson K, Reimer J, Nilsson C (2009) A Swedish family with de novo α-synuclein A53T mutation: evidence for early cortical dysfunction. Parkinsonism Relat Disord 15:627–632

    Article  PubMed Central  PubMed  Google Scholar 

  • Richfield EK, Thiruchelvam MJ, Cory-Slechta DA, Wuertzer C, Gainetdinov RR, Caron MG, Di Monte DA, Federoff HJ (2002) Behavioral and neurochemical effects of wild-type and mutated human α-synuclein in transgenic mice. Exp Neurol 175:35–48

    Article  CAS  PubMed  Google Scholar 

  • Rieker C, Dev KK, Lehnhoff K, Barbieri S, Ksiazek I, Kauffmann S, Danner S, Schell H, Boden C, Ruegg MA, Kahle PJ, van der Putten H, Shimshek DR (2011) Neuropathology in mice expressing mouse alpha-synuclein. PLoS ONE 6:e24834

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Robertson DC, Schmidt O, Ninkina N, Jones PA, Sharkey J, Buchman VL (2004) Developmental loss and resistance to MPTP toxicity of dopaminergic neurones in substantia nigra pars compacta of γ-synuclein, α-synuclein and double α/γ-synuclein null mutant mice. J Neurochem 89:1126–1136

    Article  CAS  PubMed  Google Scholar 

  • Rockenstein E, Mallory M, Hashimoto M, Song D, Shults CW, Lang I, Masliah E (2002) Differential neuropathological alterations in transgenic mice expressing α-synuclein from the platelet-derived growth factor and Thy-1 promoters. J Neurosci Res 68:568–578

    Article  CAS  PubMed  Google Scholar 

  • Rockenstein E, Nuber S, Overk CR, Ubhi K, Mante M, Patrick C, Adame A, Trejo-Morales M, Gerez J, Picotti P, Jensen PH, Campioni S, Riek R, Winkler J, Gage FH, Winner B, Masliah E (2014) Accumulation of oligomer-prone α-synuclein exacerbates synaptic and neuronal degeneration in vivo. Brain

    Google Scholar 

  • Rodriguez-Oroz MC, Jahanshahi M, Krack P, Litvan I, Macias R, Bezard E, Obeso JA (2009) Initial clinical manifestations of Parkinson’s disease: features and pathophysiological mechanisms. Lancet Neurol 8:1128–1139

    Article  CAS  PubMed  Google Scholar 

  • Rothman SM, Griffioen KJ, Vranis N, Ladenheim B, Cong W-N, Cadet J-L, Haran J, Martin B, Mattson MP (2013) Neuronal Expression of Familial Parkinson’s Disease A53T α-Synuclein Causes Early Motor Impairment, Reduced Anxiety and Potential Sleep Disturbances in Mice. J Parkinson’s Dis 3:215–229

    CAS  Google Scholar 

  • Rothman SM, Griffioen KJ, Fishbein KW, Spencer RG, Makrogiannis S, Cong W-N, Martin B, Mattson MP (2014) Metabolic abnormalities and hypoleptinemia in α-synuclein A53T mutant mice. Neurobiol Aging 35:1153–1161

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Schell H, Hasegawa T, Neumann M, Kahle PJ (2009) Nuclear and neuritic distribution of serine-129 phosphorylated α-synuclein in transgenic mice. Neuroscience 160:796–804

    Article  CAS  PubMed  Google Scholar 

  • Schell H, Boden C, Chagas AM, Kahle PJ (2012) Impaired c-fos and polo-like kinase 2 induction in the limbic system of fear-conditioned α-synuclein transgenic mice. PLoS ONE 7:e50245

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Senior SL, Ninkina N, Deacon R, Bannerman D, Buchman VL, Cragg SJ, Wade-Martins R (2008) Increased striatal dopamine release and hyperdopaminergic-like behaviour in mice lacking both alpha-synuclein and gamma-synuclein. Eur J Neurosci 27:947–957

    Article  PubMed Central  PubMed  Google Scholar 

  • Siegmund A, Langnaese K, Wotjak CT (2005) Differences in extinction of conditioned fear in C57BL/6 substrains are unrelated to expression of α-synuclein. Behav Brain Res 157:291–298

    Article  CAS  PubMed  Google Scholar 

  • Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R, Lincoln S, Crawley A, Hanson M, Maraganore D, Adler C, Cookson MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J, Gwinn-Hardy K (2003) α-synuclein locus triplication causes parkinson’s disease. Science 302:841

    Article  CAS  PubMed  Google Scholar 

  • Somme JH, Gomez-Esteban JC, Molano A, Tijero B, Lezcano E, Zarranz JJ (2011) Initial neuropsychological impairments in patients with the E46 K mutation of the α-synuclein gene (PARK 1). J Neurol Sci 310:86–89

    Article  CAS  PubMed  Google Scholar 

  • Specht CG, Schoepfer R (2004) Deletion of multimerin-1 in α-synuclein-deficient mice. Genomics 83:1176–1178

    Article  CAS  PubMed  Google Scholar 

  • Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M (1998) α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. Proc Natl Acad Sci 95:6469–6473

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Spira PJ, Sharpe DM, Halliday G, Cavanagh J, Nicholson GA (2001) Clinical and pathological features of a Parkinsonian syndrome in a family with an Ala53Thr alpha-synuclein mutation. Ann Neurol 49:313–319

    Article  CAS  PubMed  Google Scholar 

  • Stiedl O, Radulovic J, Lohmann R, Birkenfeld K, Palve M, Kammermeier J, Sananbenesi F, Spiess J (1999) Strain and substrain differences in context- and tone-dependent fear conditioning of inbred mice. Behav Brain Res 104:1–12

    Article  CAS  PubMed  Google Scholar 

  • Szegő ÉM, Gerhardt E, Outeiro TF, Kermer P (2011) Dopamine-depletion and increased α-synuclein load induce degeneration of cortical cholinergic fibers in mice. J Neurol Sci 310:90–95

    Article  PubMed  Google Scholar 

  • Taylor TN, Potgieter D, Anwar S, Senior SL, Janezic S, Threlfell S, Ryan B, Parkkinen L, Deltheil T, Cioroch M, Livieratos A, Oliver PL, Jennings KA, Davies KE, Ansorge O, Bannerman DM, Cragg SJ, Wade-Martins R (2014) Region-specific deficits in dopamine, but not norepinephrine, signaling in a novel A30P α-synuclein BAC transgenic mouse. Neurobiol Dis 62:193–207

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Thiruchelvam MJ, Powers JM, Cory-Slechta DA, Richfield EK (2004) Risk factors for dopaminergic neuron loss in human α-synuclein transgenic mice. Eur J Neurosci 19:845–854

    Article  CAS  PubMed  Google Scholar 

  • Tofaris GK, Garcia Reitböck P, Humby T, Lambourne SL, O’Connell M, Ghetti B, Gossage H, Emson PC, Wilkinson LS, Goedert M, Grazia Spillantini M (2006) Pathological changes in dopaminergic nerve cells of the substantia nigra and olfactory bulb in mice transgenic for truncated human α-synuclein(1–120): implications for Lewy Body disorders. J Neurosci 26:3942–3950

    Google Scholar 

  • Wakamatsu M, Ishii A, Iwata S, Sakagami J, Ukai Y, Ono M, Kanbe D, Muramatsu S-I, Kobayashi K, Iwatsubo T, Yoshimoto M (2008a) Selective loss of nigral dopamine neurons induced by overexpression of truncated human α-synuclein in mice. Neurobiol Aging 29:574–585

    Article  CAS  PubMed  Google Scholar 

  • Wakamatsu M, Iwata S, Funakoshi T, Yoshimoto M (2008b) Dopamine receptor agonists reverse behavioral abnormalities of α-synuclein transgenic mouse, a new model of Parkinson’s disease. J Neurosci Res 86:640–646

    Article  CAS  PubMed  Google Scholar 

  • Watson GS, Leverenz JB (2010) Profile of cognitive impairment in Parkinson’s disease. Brain Pathol 20:640–645

    Article  PubMed Central  PubMed  Google Scholar 

  • Williams-Gray CH, Foltynie T, Brayne CEG, Robbins TW, Barker RA (2007) Evolution of cognitive dysfunction in an incident Parkinson’s disease cohort. Brain. 130:1787–1798

    Article  CAS  PubMed  Google Scholar 

  • Winner B, Lie DC, Rockenstein E, Aigner R, Aigner L, Masliah E, Kuhn HG, Winkler J (2004) Human wild-type α-synuclein impairs neurogenesis. J Neuropathol Exp Neurol 63:1155–1166

    CAS  PubMed  Google Scholar 

  • Yamada M, Iwatsubo T, Mizuno Y, Mochizuki H (2004) Overexpression of α-synuclein in rat substantia nigra results in loss of dopaminergic neurons, phosphorylation of α-synuclein and activation of caspase-9: resemblance to pathogenetic changes in Parkinson’s disease. J Neurochem 91:451–461

    Article  CAS  PubMed  Google Scholar 

  • Yamaguchi K, Cochran E, Murrell J, Polymeropoulos M, Shannon K, Crowther RA, Goedert M, Ghetti B (2005) Abundant neuritic inclusions and microvacuolar changes in a case of diffuse Lewy body disease with the A53T mutation in the α-synuclein gene. Acta Neuropathol 110:298–305

    Article  PubMed  Google Scholar 

  • Yamakado H, Moriwaki Y, Yamasaki N, Miyakawa T, Kurisu J, Uemura K, Inoue H, Takahashi M, Takahashi R (2012) α-Synuclein BAC transgenic mice as a model for Parkinson’s disease manifested decreased anxiety-like behavior and hyperlocomotion. Neurosci Res 73:173–177

    Article  CAS  PubMed  Google Scholar 

  • Yang XW, Gong S (2001) An overview on the generation of BAC transgenic mice for neuroscience research. Wiley, Current Protocols in Neuroscience

    Google Scholar 

  • Yang J-H, Han S-J, Ryu JH, Jang I-S, Kim D-H (2009) Ginsenoside Rh2 Ameliorates Scopolamine-Induced Learning Deficit in Mice. Biol Pharm Bull 32:1710–1715

    Article  CAS  PubMed  Google Scholar 

  • Yarnall AJ, Rochester L, Burn DJ (2013) Mild cognitive impairment in Parkinson’s disease. Age Ageing 42:567–576

    Article  PubMed  Google Scholar 

  • Zhou W, Milder JB, Freed CR (2008) Transgenic mice overexpressing tyrosine-to-cysteine mutant human α-synuclein: a progressive nurodegenerative model of diffuse Lewy body disease. J Biol Chem 283:9863–9870

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, USA

    Asa Hatami & Marie-Francoise Chesselet

Authors
  1. Asa Hatami
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marie-Francoise Chesselet
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marie-Francoise Chesselet .

Editor information

Editors and Affiliations

  1. Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tübingen, Germany

    Hoa Huu Phuc Nguyen

  2. Dept of Experimental Medical Science, Lund University, Lund, Sweden

    M. Angela Cenci

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Hatami, A., Chesselet, MF. (2014). Transgenic Rodent Models to Study Alpha-Synuclein Pathogenesis, with a Focus on Cognitive Deficits. In: Nguyen, H., Cenci, M. (eds) Behavioral Neurobiology of Huntington's Disease and Parkinson's Disease. Current Topics in Behavioral Neurosciences, vol 22. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7854_2014_355

Download citation

Publish with us

Policies and ethics

Search

Navigation