TY - JOUR
T1 - Age-related shift in LTD is dependent on neuronal adenosine A2A receptors interplay with mGluR5 and NMDA receptors
AU - Temido-Ferreira, Mariana
AU - Ferreira, Diana G.
AU - Batalha, Vânia L.
AU - Marques-Morgado, Inês
AU - Coelho, Joana E.
AU - Pereira, Pedro
AU - Gomes, Rui
AU - Pinto, Andreia
AU - Carvalho, Sara
AU - Canas, Paula M.
AU - Cuvelier, Laetitia
AU - Buée-Scherrer, Valerie
AU - Faivre, Emilie
AU - Baqi, Younis
AU - Müller, Christa E.
AU - Pimentel, José
AU - Schiffmann, Serge N.
AU - Buée, Luc
AU - Bader, Michael
AU - Outeiro, Tiago F.
AU - Blum, David
AU - Cunha, Rodrigo A.
AU - Marie, Hélène
AU - Pousinha, Paula A.
AU - Lopes, Luísa V.
N1 - Publisher Copyright:
© 2018, The Author(s).
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
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U2 - 10.1038/s41380-018-0110-9
DO - 10.1038/s41380-018-0110-9
M3 - Article
AN - SCOPUS:85049064131
SN - 1359-4184
VL - 25
SP - 1876
EP - 1900
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 8
ER -