Journal
JOURNAL OF NEUROCHEMISTRY
Volume 120, Issue 4, Pages 541-551Publisher
WILEY
DOI: 10.1111/j.1471-4159.2011.07608.x
Keywords
calcium; calmodulin-dependent protein kinase II; cognitive deficits; long-term potentiation; MPTP; Parkinson's disease
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Funding
- Ministry of Education, Culture, Sports, Science and Technology
- Ministry of Health and Welfare of Japan [22390109, 20790398]
- Pharmacological Research Foundation, Tokyo
- Research Foundation for Pharmaceutical Sciences
- Smoking Research Foundation
- Takeda Science Foundation
- NISHINOMIYA Basic Research Fund (Japan)
- HIROMI Medical Research Foundation
- Grants-in-Aid for Scientific Research [22390109, 20790398] Funding Source: KAKEN
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Parkinsons disease (PD) patients frequently reveal deficit in cognitive functions during the early stage in PD. The dopaminergic neurotoxin, MPTP-induced neurodegeneration causes an injury of the basal ganglia and is associated with PD-like behaviors. In this study, we demonstrated that deficits in cognitive functions in MPTP-treated mice were associated with reduced calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation and impaired long-term potentiation (LTP) induction in the hippocampal CA1 region. Mice were injected once a day for 5 days with MPTP (25 mg/kg i.p.). The impaired motor coordination was observed 1 or 2 week after MPTP treatment as assessed by rota-rod and beam-walking tasks. In immunoblotting analyses, the levels of tyrosine hydroxylase protein and CaMKII autophosphorylation in the striatum were significantly decreased 1 week after MPTP treatment. By contrast, deficits of cognitive functions were observed 34 weeks after MPTP treatment as assessed by novel object recognition and passive avoidance tasks but not Y-maze task. Impaired LTP in the hippocampal CA1 region was also observed in MPTP-treated mice. Concomitant with impaired LTP induction, CaMKII autophosphorylation was significantly decreased 3 weeks after MPTP treatment in the hippocampal CA1 region. Finally, the reduced CaMKII autophosphorylation was closely associated with reduced AMPA-type glutamate receptor subunit 1 (GluR1; Ser-831) phosphorylation in the hippocampal CA1 region of MPTP-treated mice. Taken together, decreased CaMKII activity with concomitant impaired LTP induction in the hippocampus likely account for the learning disability observed in MPTP-treated mice.
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