Journal
NEUROBIOLOGY OF DISEASE
Volume 67, Issue -, Pages 191-202Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2014.03.004
Keywords
Parkinson's disease; Microglia; Adenosine A(2A) receptor; Preladenant; Acute brain slice; Imaging; Neuroinflammation
Categories
Funding
- NINDS NRSA [F31NS076215]
- NIEHS Toxicology institutional training grant [T32ES12870]
- NIH Pharmacological Sciences institutional training grant [T32GM008602]
- Emory University Udall Center for Parkinson's Disease Research [NIH/NINDS P50-NS071669]
- Alzheimer's Disease Research Center [NIH P50 AG025688]
- Yerkes Primate Center NIH base grant [RR00165]
- Emory University Integrated Cellular Imaging Microscopy Core
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Microglia, the immune cells of the central nervous system, constantly survey the parenchyma in the healthy brain to maintain homeostasis. When a disturbance, such as cell death, results in ATP release in vivo, microglial processes respond by utilizing P2Y(12) purinergic receptors to trigger extension toward the site of damage. Processes ultimately surround the injury site, preventing the spread of harmful cellular constituents and assisting with tissue repair. In contrast to the healthy brain, many neurodegenerative diseases, including Parkinson's disease, are characterized by the presence of neuroinflammation. Yet, the ability of microglia to respond to tissue damage under pro-inflammatory conditions has not been well studied. To assess the ability of microglia to respond to tissue injury and localized cell death in the context of Parkinson's disease, we performed confocal imaging of acute brain slices from mice with microglia-specific green fluorescent protein expression. Microglia in coronal slices containing the substantia nigra extend processes toward a mechanical injury in a P2Y(12) receptor-dependent manner. However, microglia in mice treated for 5 days with 20 mg/kg/day 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) show significantly reduced process displacement toward the injury compared to microglia in control animals. Pre-treatment of slices from MPTP-injected mice with the A(2A) receptor-selective antagonist preladenant restores the ability of activated microglia to respond to tissue damage. These data support the hypothesis that chronic inflammation impedes microglial motility in response to further injury, such as cell death, and suggest that some aspects of the neuroprotection observed with adenosine A(2A) receptor antagonists may involve direct or indirect actions at microglia. (C) 2014 Elsevier Inc. All rights reserved.
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