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Mol Psychiatry. 2018 Jun 27. doi: 10.1038/s41380-018-0110-9. [Epub ahead of print]

Age-related shift in LTD is dependent on neuronal adenosine A2A receptors interplay with mGluR5 and NMDA receptors.

Author information

1
Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Universidade de Lisboa, 1649-028, Lisbon, Portugal.
2
Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Waldweg 33, 37073, Göttingen, Germany.
3
Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal.
4
MedInUP-Center for Drug Discovery and Innovative Medicines, University of Porto, 4200-450, Porto, Portugal.
5
Laboratory of Neuropathology, Department of Neurosciences, Hospital de Santa Maria, CHLN, EPE, 1649-035, Lisbon, Portugal.
6
Faculdade de Ciências da Universidade de Lisboa, 1749-016, Lisbon, Portugal.
7
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.
8
Faculty of Medicine, University of Coimbra, 3004-504, Coimbra, Portugal.
9
Laboratory of Neurophysiology, ULB Neuroscience Institute, Université Libre de Bruxelles (ULB), 1070, Brussels, Belgium.
10
Université de Lille, Institut National de la Santé et de la Recherche Medicale (INSERM), CHU Lille, UMR-S 1172 JPArc, "Alzheimer & Tauopathie", LabEx DISTALZ, Lille, France.
11
PharmaCenter Bonn, Pharmazeutische Chemie I, Pharmazeutisches Institut, University of Bonn, Bonn, Germany.
12
Department of Chemistry, Faculty of Science, Sultan Qaboos University, PO Box 36, Postal Code 123, Muscat, Oman.
13
Max-Delbrück-Center for Molecular Medicine (MDC), 13125, Berlin, Germany.
14
Charité-University Medicine, 10117, Berlin, Germany.
15
Institute of Biology, University of Lübeck, 23652, Lübeck, Germany.
16
Max Planck Institute for Experimental Medicine, 37075, Göttingen, Germany.
17
CEDOC, Chronic Diseases Research Center, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1150-082, Lisbon, Portugal.
18
Institute of Neuroscience, The Medical School, Newcastle University, Framlington Place, Newcastle Upon Tyne, NE2 4HH, United Kingdom.
19
Université Côte d'Azur, CNRS UMR7276, IPMC, 06560, Valbonne, France.
20
Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Universidade de Lisboa, 1649-028, Lisbon, Portugal. lvlopes@medicina.ulisboa.pt.

Abstract

Synaptic dysfunction plays a central role in Alzheimer's disease (AD), since it drives the cognitive decline. An association between a polymorphism of the adenosine A2A receptor (A2AR) encoding gene-ADORA2A, and hippocampal volume in AD patients was recently described. In this study, we explore the synaptic function of A2AR in age-related conditions. We report, for the first time, a significant overexpression of A2AR in hippocampal neurons of aged humans, which is aggravated in AD patients. A similar profile of A2AR overexpression in rats was sufficient to drive age-like memory impairments in young animals and to uncover a hippocampal LTD-to-LTP shift. This was accompanied by increased NMDA receptor gating, dependent on mGluR5 and linked to enhanced Ca2+ influx. We confirmed the same plasticity shift in memory-impaired aged rats and APP/PS1 mice modeling AD, which was rescued upon A2AR blockade. This A2AR/mGluR5/NMDAR interaction might prove a suitable alternative for regulating aberrant mGluR5/NMDAR signaling in AD without disrupting their constitutive activity.

PMID:
29950682
DOI:
10.1038/s41380-018-0110-9

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