Journal
JOURNAL OF PARKINSONS DISEASE
Volume 3, Issue 2, Pages 215-229Publisher
IOS PRESS
DOI: 10.3233/JPD-120130
Keywords
Parkinson's disease; alpha-synuclein; hypothalamus; dopamine; circadian; stride length; anxiety; sleep; serotonin
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Funding
- Intramural Research Program of the NIH, National Institute on Aging
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Background: Mutations in the human alpha-synuclein gene lead to early-onset Parkinson's disease (PD); however, phenotypes of alpha-synuclein mutant mice vary depending upon the promoter driving transgene expression. Objective: The goal of this study was to characterize behavior and neurochemical alterations in mice expressing mutant (A53T) human alpha-synuclein, controlled by a neuron-specific Thy-1 promoter. Our data provide important additional phenotypic and biochemical characterization of a previously generated model of PD. Methods: A53T (SNCA) and wild type (WT) littermate mice were evaluated for motor function (rotarod and stride length) and anxiety (elevated plus maze and open field) every 2 weeks. At 24 weeks mice were evaluated in a Comprehensive Lab Animal Monitoring System (CLAMS). A separate cohort of mice were euthanized at 12, 24 and 36 weeks for immunoblot analysis of alpha-synuclein, dopamine transporter (DAT) and tyrosine hydroxylase (TH) in the striatum, and hypothalamic serotonin and metabolites were measured. Results: SNCA mice display significant motor deficits at 14-18 weeks of age compared to WT mice, which progress over time. CLAMS analysis revealed an increase in activity during the dark phase and a reduction in overall estimated sleep time for SNCA mice compared to WT consistent with clinical reports of sleep abnormalities in PD. A transient change in the levels of DAT appeared at 12 weeks in the striatum and serotonin levels were also altered in the hypothalamus at this time point. Conclusions: This PD model displays consistent and clinically relevant motor and sleep phenotypes. Anxiety phenotypes are consistent with other alpha-synuclein based PD models yet incongruous with typical clinical symptoms. Early increases in serotonin levels potentially explain reductions in anxiety behaviors and sleep.
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