title: Cognitive dysfunction precedes the onset of motor symptoms in the MitoPark mouse model of Parkinson's disease.
abstract: Parkinson's disease (PD) is a neurodegenerative disorder primarily characterized by progressive loss of dopamine neurons, leading to loss of motor coordination. However, PD is associated with a high rate of non-motor neuropsychiatric comorbities that often develop before the onset of movement symptoms. The MitoPark transgenic mouse model is the first to recapitulate the cardinal clinical features, namely progressive neurodegeneration and death of neurons, loss of motor function and therapeutic response to L-DOPA. To investigate whether MitoPark mice exhibit early onset of cognitive impairment, a non-motor neuropsychiatric comorbidity, we measured performance on a spatial learning and memory task before (∼8 weeks) or after (∼20 weeks) the onset of locomotor decline in MitoPark mice or in littermate controls. Consistent with previous studies, we established that a progressive loss of spontaneous locomotor activity began at 12 weeks of age, which was followed by progressive loss of body weight beginning at 16-20 weeks. Spatial learning and memory was measured using the Barnes Maze. By 20 weeks of age, MitoPark mice displayed a substantial reduction in overall locomotor activity that impaired their ability to perform the task. However, in the 8-week-old mice, locomotor activity was no different between genotypes, yet MitoPark mice took longer, traveled further and committed more errors than same age control mice, while learning to successfully navigate the maze. The modest between-day learning deficit of MitoPark mice was characterized by impaired within-day learning during the first two days of testing. No difference was observed between genotypes during probe trials conducted one or twelve days after the final acquisition test. Additionally, 8-week-old MitoPark mice exhibited impaired novel object recognition when compared to control mice. Together, these data establish that mild cognitive impairment precedes the loss of motor function in a novel rodent model of PD, which may provide unique opportunities for therapeutic development.
authors: Department of Pharmacology, The University of Texas Health Science Center, San Antonio, Texas, United States of America ; Department of Medicine, The University of Texas Health Science Center, San Antonio, Texas, United States of America ; Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, P.R. China.
authors: Xiuhua
authors: X
authors: Li
authors: Laney
authors: L
authors: Redus
authors: Cang
authors: C
authors: Chen
authors: Paul A
authors: PA
authors: Martinez
authors: Randy
authors: R
authors: Strong
authors: Senlin
authors: S
authors: Li
authors: Jason C
authors: JC
authors: O'Connor
mesh_terms: D000818:Animals; D001835:Body Weight; D003071:Cognition; D004195:Disease Models, Animal; D005260:Female; D005838:Genotype; D008297:Male; D018782:Maze Learning; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity; D010300:Parkinson Disease / Q000235:genetics / Q000503:physiopathology*; D010641:Phenotype; D013037:Spatial Behavior; D013997:Time Factors
references: Mov Disord. 2013 May;28(5):663-7
references: 23238827
references: Curr Med Chem. 2010;17(28):3253-61
references: 20666719
references: J Neurochem. 2012 Feb;120(4):541-51
references: 22136399
references: Acta Neurochir Suppl. 2008;101:89-92
references: 18642640
references: Brain Behav Immun. 2013 Aug;32:63-9
references: 23454036
references: J Cogn Neurosci. 2011 Oct;23(10):2797-810
references: 21254797
references: Lancet Neurol. 2006 Mar;5(3):235-45
references: 16488379
references: Proc Natl Acad Sci U S A. 2007 Jan 23;104(4):1325-30
references: 17227870
references: Drugs Aging. 2000 May;16(5):365-79
references: 10917074
references: J Immunol. 2009 Mar 1;182(5):3202-12
references: 19234218
references: Cogn Process. 2012 May;13(2):93-110
references: 22160349
references: Brain Behav Immun. 2010 Aug;24(6):1008-17
references: 20399847
references: Mov Disord. 2001 May;16(3):507-10
references: 11391746
references: FASEB J. 2011 Apr;25(4):1333-44
references: 21233488
references: J Neurosci. 2009 Apr 1;29(13):4200-9
references: 19339614
references: Behav Neurosci. 2006 Dec;120(6):1279-84
references: 17201473
references: Behav Neurol. 2006;17(1):43-51
references: 16720959
references: Neurology. 2013 Feb 12;80(7):627-33
references: 23345637
references: Behav Brain Res. 2011 Sep 12;222(1):169-75
references: 21443906
references: Parkinsonism Relat Disord. 2009 Dec;15 Suppl 3:S185-8
references: 20082987
references: Neurology. 2009 Nov 3;73(18):1469-77
references: 19884574
references: Neurology. 2012 Sep 25;79(13):1323-31
references: 22972639
references: Genes Brain Behav. 2010 Mar 1;9(2):173-81
references: 20002202
references: Parkinsonism Relat Disord. 2007 Aug;13(6):323-32
references: 17349813
references: Neuropsychologia. 2012 Nov;50(13):3141-55
references: 22634248
references: Mov Disord. 2009 May 15;24(7):1028-33
references: 19353704