Norepinephrine loss produces more profound motor deficits than MPTP treatment in mice
Although Parkinson's disease (PD) is characterized primarily by loss of nigrostriatal dopaminergic neurons, there is a concomitant loss of norepinephrine (NE) neurons in the locus coeruleus. Dopaminergic lesions induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are commonly used to...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 34; pp. 13804 - 13809 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences
21.08.2007
National Acad Sciences |
Subjects | |
Online Access | Get full text |
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Summary: | Although Parkinson's disease (PD) is characterized primarily by loss of nigrostriatal dopaminergic neurons, there is a concomitant loss of norepinephrine (NE) neurons in the locus coeruleus. Dopaminergic lesions induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are commonly used to model PD, and although MPTP effectively mimics the dopaminergic neuropathology of PD in mice, it fails to produce PD-like motor deficits. We hypothesized that MPTP is unable to recapitulate the motor abnormalities of PD either because the behavioral paradigms used to measure coordinated behavior in mice are not sensitive enough or because MPTP in the absence of NE loss is insufficient to impair motor control. We tested both possibilities by developing a battery of coordinated movement tests and examining motor deficits in dopamine β-hydroxylase knockout (Dbh-/-) mice that lack NE altogether. We detected no motor abnormalities in MPTP-treated control mice, despite an 80% loss of striatal dopamine (DA) terminals. Dbh-/- mice, on the other hand, were impaired in most tests and also displayed spontaneous dyskinesias, despite their normal striatal DA content. A subset of these impairments was recapitulated in control mice with 80% NE lesions and reversed in Dbh-/- mice, either by restoration of NE or treatment with a DA agonist. MPTP did not exacerbate baseline motor deficits in Dbh-/- mice. Finally, striatal levels of phospho-ERK-1/2 and ΔFosB/FosB, proteins which are associated with PD and dyskinesias, were elevated in Dbh-/- mice. These results suggest that loss of locus coeruleus neurons contributes to motor dysfunction in PD. |
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Bibliography: | Edited by Richard D. Palmiter, University of Washington School of Medicine, Seattle, WA, and approved June 25, 2007 Author contributions: K.S.R., G.L.E., K.G.F., G.W.M., and D.W. designed research; K.S.R., K.G.F., and L.C.L. performed research; G.L.E., K.G.F., and L.C.L. contributed new reagents/analytic tools; K.S.R. and D.W. analyzed data; and K.S.R., G.L.E., K.G.F., G.W.M., and D.W. wrote the paper. |
ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.0702753104 |