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

Mariana Temido-Ferreira, Diana G Ferreira, Vânia L Batalha, Inês Marques-Morgado, Joana E Coelho, Pedro Pereira, Rui Gomes, Andreia Pinto, Sara Carvalho, Paula M Canas, Laetitia Cuvelier, Valerie Buée-Scherrer, Emilie Faivre, Younis Baqi, Christa E Müller, José Pimentel, Serge N Schiffmann, Luc Buée, Michael Bader, Tiago F OuteiroDavid Blum, Rodrigo A Cunha, Hélène Marie, Paula A Pousinha, Luísa V Lopes

Research output: Contribution to journalArticlepeer-review

80 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1876-1900
JournalMolecular Psychiatry
Issue number8
Early online date27 Jun 2018
Publication statusPublished - Aug 2020


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