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

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Ferreira, Mariana | Ferreira, Diana | Batalha, Vânia | Marques-Morgado, Inês | Coelho, Joana | Pereira, Pedro | Gomes, Rui | Pinto, Andreia | Carvalho, Sara | Canas, Paula | Cuvelier, Laetitia | Buée, Valerie | Faivre, Emilie | Baqi, Younis | Müller, Christa | Pimentel, José | Schiffmann, Serge, N. | Buée, Luc | Bader, Michael | Outeiro, Tiago | Blum, David | Cunha, Rodrigo | Marie, Hélène | Pousinha, Paula | Lopes, Luísa

Edité par CCSD ; Nature Publishing Group -

International audience. 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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