Abstract
Growing evidence suggests, as Parkinson’s disease (PD) progresses, that its non-motor symptoms appear prior to or in parallel with its motor deficits. Alpha-synuclein A53T transgenic mouse (A53T) is an essential tool to investigate the onsets and the extents of PD non-motor symptoms. Our aim is to investigate spatial learning and memory ability in A53T mice. In our rotarod tests, no motor coordination impairments were detected in mice of 3, 6, 9, and 12 months old. We then investigated their spatial learning and memory ability through Morris water maze in 3- and 9-month-old mice. No significant difference in escape latency was detected among the A53T mice and the control mice. However, an unexpected improvement in spatial learning and memory ability was observed in the probe session among the A53T mice. Reversal learning by Morris water maze also indicated that 3- and 9-month-old A53T mice exhibited a better cognitive flexibility compared to their littermate controls. Further studies by western blots showed that alpha-synuclein expressions in hippocampus of the A53T mice were noticeably up-regulated. The immunofluorescence staining of 5-bromo-2-deoxyuridine (Brdu) and doublecortin (DCX) demonstrated that neither the Brdu-positive neurons nor the Brdu/DCX positive neurons in hippocampus were significantly altered between the two groups. These results suggest that our A53T mice exhibit improved spatial learning and memory ability prior to their motor coordination deficits. These results are not induced by neurogenesis in the hippocampus.
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Bellucci A, Navarria L, Zaltieri M, Missale C, Spano P (2012) Alpha-synuclein synaptic pathology and its implications in the development of novel therapeutic approaches to cure Parkinson’s disease. Brain Res 1432:95–113
Cabin DE, Shimazu K, Murphy D, Cole NB, Gottschalk W, McIlwain KL, Orrison B, Chen A, Ellis CE, Paylor R, Lu B, Nussbaum RL (2002) Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking alpha-synuclein. J Neurosci 22(20):8797–8807
Calo L, Wegrzynowicz M, Santivanez-Perez J, Grazia Spillantini M (2016) Synaptic failure and alpha-synuclein. Mov Disord 31(2):169–177
Chen PE, Specht CG, Morris RG, Schoepfer R (2002) Spatial learning is unimpaired in mice containing a deletion of the alpha-synuclein locus. Eur J Neurosci 16(1):154–158
Clayton DF, George JM (1999) Synucleins in synaptic plasticity and neurodegenerative disorders. J Neurosci Res 58(1):120–129
Ferrer I, Lopez-Gonzalez I, Carmona M, Dalfo E, Pujol A, Martinez A (2012) Neurochemistry and the non-motor aspects of PD. Neurobiol Dis 46(3):508–526
Garthe A, Behr J, Kempermann G (2009) Adult-generated hippocampal neurons allow the flexible use of spatially precise learning strategies. PLoS One 4(5):e5464
George JM, Jin H, Woods WS, Clayton DF (1995) Characterization of a novel protein regulated during the critical period for song learning in the zebra finch. Neuron 15(2):361–372
George S, van den Buuse M, San Mok S, Masters CL, Li QX, Culvenor JG (2008) Alpha-synuclein transgenic mice exhibit reduced anxiety-like behaviour. Exp Neurol 210(2):788–792
Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, Lee VM (2002) Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron 34(4):521–533
Graham DR, Sidhu A (2010) Mice expressing the A53T mutant form of human alpha-synuclein exhibit hyperactivity and reduced anxiety-like behavior. J Neurosci Res 88(8):1777–1783
Guerreiro PS, Coelho JE, Sousa-Lima I, Macedo P, Lopes LV, Outeiro TF, Pais TF (2017) Mutant A53T alpha-synuclein improves rotarod performance before motor deficits and affects metabolic pathways. Neuromol Med 19(1):113–121
Hartman VN, Miller MA, Clayton DF, Liu WC, Kroodsma DE, Brenowitz EA (2001) Testosterone regulates alpha-synuclein mRNA in the avian song system. Neuroreport 12(5):943–946
Jia F, Song N, Zhao C, Xie J, Jiang H (2014) Unexpected improvements of spatial learning and memory abilities in chronic rotenone intoxicated mice. PLoS One 9(3):e91641
Kotzbauer PT, Giasson BI, Kravitz AV, Golbe LI, Mark MH, Trojanowski JQ, Lee VM (2004) Fibrillization of alpha-synuclein and tau in familial Parkinson’s disease caused by the A53T alpha-synuclein mutation. Exp Neurol 187(2):279–288
Lam HA, Wu N, Cely I, Kelly RL, Hean S, Richter F, Magen I, Cepeda C, Ackerson LC, Walwyn W, Masliah E, Chesselet MF, 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 alpha-synuclein. J Neurosci Res 89(7):1091–1102
Lim Y, Kehm VM, Lee EB, Soper JH, Li C, Trojanowski JQ, Lee VM (2012) Alpha-Syn suppression reverses synaptic and memory defects in a mouse model of dementia with Lewy bodies. J Neurosci 31(27):10076–10087
Magen I, Fleming SM, Zhu C, Garcia EC, Cardiff KM, Dinh D, De La Rosa K, Sanchez M, Torres ER, Masliah E, Jentsch JD, Chesselet MF (2012) Cognitive deficits in a mouse model of pre-manifest Parkinson’s disease. Eur J Neurosci 35(6):870–882
Ossig C, Sippel D, Fauser M, Gandor F, Jost WH, Ebersbach G, Storch A (2017) Timing and kinetics of nonmotor fluctuations in advanced Parkinson’s disease. J Parkinsons Dis. https://doi.org/10.3233/JPD-160996
Palmeri R, Lo Buono V, Corallo F, Foti M, Di Lorenzo G, Bramanti P, Marino S (2017) Nonmotor symptoms in parkinson disease: a descriptive review on social cognition ability. J Geriatr Psychiatry Neurol 30(2):109–121
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 DW, Dunlop J (2013) Behavioral characterization of A53T mice reveals early and late stage deficits related to Parkinson’s disease. PLoS One 8(8):e70274
Petersen K, Olesen OF, Mikkelsen JD (1999) Developmental expression of alpha-synuclein in rat hippocampus and cerebral cortex. Neuroscience 91(2):651–659
Poirier AA, Aube B, Cote M, Morin N, Di Paolo T, Soulet D (2016) Gastrointestinal dysfunctions in Parkinson’s disease: symptoms and treatments. Parkinsons Dis 2016:6762528
Recchia A, Debetto P, Negro A, Guidolin D, Skaper SD, Giusti P (2004) Alpha-synuclein and Parkinson’s disease. FASEB J 18(6):617–626
Savitt JM, Dawson VL, Dawson TM (2006) Diagnosis and treatment of Parkinson disease: molecules to medicine. J Clin Invest 116(7):1744–1754
Trinchero MF, Koehl M, Bechakra M, Delage P, Charrier V, Grosjean N, Ladeveze E, Schinder AF, Abrous DN (2015) Effects of spaced learning in the water maze on development of dentate granule cells generated in adult mice. Hippocampus 25(11):1314–1326
Trojanowski JQ, Goedert M, Iwatsubo T, Lee VM (1998) Fatal attractions: abnormal protein aggregation and neuron death in Parkinson’s disease and Lewy body dementia. Cell Death Differ 5(10):832–837
Winner B, Regensburger M, Schreglmann S, Boyer L, Prots I, Rockenstein E, Mante M, Zhao C, Winkler J, Masliah E, Gage FH (2012) Role of alpha-synuclein in adult neurogenesis and neuronal maturation in the dentate gyrus. J Neurosci 32(47):16906–16916
Yang Y, Tang BS, Guo JF (2017) Parkinson’s disease and cognitive impairment. Parkinsons Dis 2016:6734678
Zhang S, Xiao Q, Le W (2015) Olfactory dysfunction and neurotransmitter disturbance in olfactory bulb of transgenic mice expressing human A53T mutant alpha-synuclein. PLoS One 10(3):e0119928
Zhang TM, Yu SY, Guo P, Du Y, Hu Y, Piao YS, Zuo LJ, Lian TH, Wang RD, Yu QJ, Jin Z, Zhang W (2016) Nonmotor symptoms in patients with Parkinson disease: A cross-sectional observational study. Medicine (Baltimore) 95(50):e5400
Zhou Y, Takahashi E, Li W, Halt A, Wiltgen B, Ehninger D, Li GD, Hell JW, Kennedy MB, Silva AJ (2007) Interactions between the NR2B receptor and CaMKII modulate synaptic plasticity and spatial learning. J Neurosci 27(50):13843–13853
Acknowledgements
This study was supported by grants from National Natural Science Foundation of China (Grant no. 81671249), China Postdoctoral Foundation (Grant no. 2015M580572), and Postdoctoral Foundation of Shandong Province and Qingdao city (Grant nos. 201502012, 2015156). The authors declared that no competing interests exist.
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All the authors mentioned above participated in this work. QL, YX, and WP performed research, QL, YX, and ZM analyzed data. ZM designed research and wrote the paper.
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Liu, Q., Xu, Y., Wan, W. et al. An unexpected improvement in spatial learning and memory ability in alpha-synuclein A53T transgenic mice. J Neural Transm 125, 203–210 (2018). https://doi.org/10.1007/s00702-017-1819-3
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DOI: https://doi.org/10.1007/s00702-017-1819-3