Adenosine A2A Receptor in the Monkey Basal Ganglia: Ultrastructural Localization and Colocalization With the Metabotropic Glutamate Receptor 5 in the Striatum

• Type of Material: Article
• Authors: James W. Bogenpohl, Emory University; Stefanie L. Ritter, Emory University; Randy A Hall, Emory University; Yoland Smith, Emory University
• Language: English
• Date: 2012-02-15
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2011 Wiley Periodicals, Inc.
• Final Published Version (URL): http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338154/
• Title of Journal or Parent Work: Journal of Comparative Neurology
• ISSN: 0021-9967
• Volume: 520
• Issue: 3
• Start Page: 570
• End Page: 589
• Grant/Funding Information: Grant sponsor: National Parkinson Foundation; Grant sponsor: National Institutes of Health; Grant number: RR00165 (to the Yerkes Primate Center); Grant sponsor: National Research Service Award; Grant number: F31 NS061520-01A2 (to J.W.B.); Grant sponsor: UDALL Parkinson’s Disease Center; Grant number: P50 NS071669.
• Keywords: putamen; primate; globus pallidus; immunogold; Parkinson’s disease; mGluR5; substantia nigra

Abstract

The adenosine A2A receptor (A2AR) is a potential drug target for the treatment of Parkinson’s disease and other neurological disorders. In rodents, the therapeutic efficacy of A2AR modulation is improved by concomitant modulation of the metabotropic glutamate receptor 5 (mGluR5). To elucidate the anatomical substrate(s) through which these therapeutic benefits could be mediated, pre-embedding electron microscopy immunohistochemistry was used to conduct a detailed, quantitative ultrastructural analysis of A2AR localization in the primate basal ganglia and to assess the degree of A2AR/mGluR5 colocalization in the striatum. A2AR immunoreactivity was found at the highest levels in the striatum and external globus pallidus (GPe). However, the monkey, but not the rat, substantia nigra pars reticulata (SNr) also harbored a significant level of neuropil A2AR immunoreactivity. At the electron microscopic level, striatal A2AR labeling was most commonly localized in postsynaptic elements (58% ± 3% of labeled elements), whereas, in the GPe and SNr, the labeling was mainly presynaptic (71% ± 5%) or glial (27% ± 6%). In both striatal and pallidal structures, putative inhibitory and excitatory terminals displayed A2AR immunoreactivity. Striatal A2AR/mGluR5 colocalization was commonly found; 60–70% of A2AR-immunoreactive dendrites or spines in the monkey striatum coexpress mGluR5. These findings provide the first detailed account of the ultrastructural localization of A2AR in the primate basal ganglia and demonstrate that A2AR and mGluR5 are located to interact functionally in dendrites and spines of striatal neurons. Together, these data foster a deeper understanding of the substrates through which A2AR could regulate primate basal ganglia function and potentially mediate its therapeutic effects in parkinsonism.