The Journal of Neuroscience, March 21, 2007, 27(12):3328-3337; doi:10.1523/JNEUROSCI.5321-06.2007
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Neurobiology of Disease
Involvement of Interferon-
in Microglial-Mediated Loss of Dopaminergic Neurons
Matthew P. Mount,1
Arman Lira,1
David Grimes,1
Patrice D. Smith,1
Sylvie Faucher,2
Ruth Slack,1
Hymie Anisman,3
Shawn Hayley,1,3 * and
David S. Park1 *
1Ottawa Health Research Institute, Neuroscience Group, Ottawa, Ontario, Canada K1H 8M5, 2National Human Immunodeficiency Virus Immunology Laboratory, Centre for Infectious Disease Prevention and Control, Ottawa, Ontario, Canada K1A 0K9, and 3Institute of Neuroscience, Carleton University, Ottawa, Ontario, Canada K1S 5B6
Correspondence should be addressed to Dr. David S. Park, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5. Email: dpark{at}uottawa.ca
Growing evidence implicates microglia in the loss of dopaminergic neurons in Parkinson's disease (PD). However, factors mediating microglial activation in PD are poorly understood. Proinflammatory cytokines, such as interferon-
(IFN-), orchestrate the actions of microglia. We report here that PD patients express significantly elevated levels of IFN- in their blood plasma. After this initial finding, we found that IFN--deficient mice displayed attenuated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced substantia nigra pars compacta dopaminergic cell loss along with reduced loss of striatal tyrosine hydroxylase and dopamine transporter fiber density. MPTP-induced depletion of striatal dopamine and its metabolite DOPAC (3,4-dihydroxyphenylacetic acid), as well as 
FosB, a marker of postsynaptic dysfunction, were also attenuated in these knock-out mice. Consistent with the role for IFN- in microglial activation, MPTP-induced morphological activation of microglia was abrogated compared with wild-type mice. To examine more mechanistically the role of IFN- in microglial activation, we evaluated the interactions between microglia and dopaminergic neurons in an in vitro mixed microglia/midbrain neuron rotenone-induced death paradigm. In this in vitro paradigm, dopaminergic neurons are selectively damaged by rotenone. Exogenous IFN- ligand alone and without rotenone resulted in dopaminergic cell loss, but only in the presence of microglia. The addition of an IFN- neutralizing antibody attenuated neuronal loss as a result of rotenone treatment. The presence of only wild-type microglia and not those deficient in IFN- receptor elicited significant dopaminergic cell loss when exposed to rotenone. Neurons deficient in IFN- receptor, however, did not display increased resistance to death. Finally, levels of IFN- message increased in microglia in response to rotenone. Together, these data suggest that IFN- participates in death of dopaminergic neurons by regulating microglial activity.
Key words: interferon- (IFN-); Parkinson's disease; neurodegeneration; dopamine; cytokine; microglia; 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
Received Nov. 7, 2005;
revised Feb. 16, 2007;
accepted Feb. 18, 2007.
Correspondence should be addressed to Dr. David S. Park, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5. Email: dpark{at}uottawa.ca
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