Adenosine A(2A) receptor antagonism reverses inflammation-induced impairment of microglial process extension in a model of Parkinson's disease

• Type of Material: Article
• Authors: Stefka Gyoneva, Emory University; Lauren Shapiro, Emory University; Carlos Lazo, Emory University; Ethel Garnier-Amblard, Emory University; Yoland Smith, Emory University; Gary W Miller, Emory University; Stephen Traynelis, Emory University
• Language: English
• Date: 2014-07-01
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.nbd.2014.03.004
• Title of Journal or Parent Work: Neurobiology of Disease
• ISSN: 0969-9961
• Volume: 67
• Start Page: 191
• End Page: 202
• Grant/Funding Information: Funding was provided by NINDS NRSA (F31NS076215, S.G.); NIEHS Toxicology institutional training grant (T32ES12870, S.G.); NIH Pharmacological Sciences institutional training grant (T32GM008602, S.G.); a pilot grant from the Emory University Udall Center for Parkinson’s Disease Research (NIH/NINDS P50-NS071669, S.F.T); the Alzheimer’s Disease Research Center (NIHP50 AG025688, S.F.T.); the Yerkes Primate Center NIH base grant (RR00165, Y.S.); and the Emory University Integrated Cellular Imaging Microscopy Core.
• Keywords: GROWTH-FACTOR-ALPHA; 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE EXPOSURE; DOPAMINE; Neurosciences; Neurosciences & Neurology; CAFFEINE; Preladenant; ACTIVATION; SUBSTANTIA-NIGRA; Acute brain slice; Microglia; Adenosine A(2A) receptor; Science & Technology; Imaging; IN-VIVO; CEREBROSPINAL-FLUID; Life Sciences & Biomedicine; REACTIVE MICROGLIA; Parkinson's disease; BRAIN; Neuroinflammation
• Research Categories: Health Sciences, Pharmacology; Environmental Sciences; Biology, Neuroscience

Abstract

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 P2Y12 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 P2Y12 receptor-dependent manner. However, microglia in mice treated for 5days with 20mg/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 A2A 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 A2A receptor antagonists may involve direct or indirect actions at microglia.