Age-related shift in LTD is dependent on neuronal adenosine A2A 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 journalArticle

31 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1-25
Number of pages25
JournalMolecular Psychiatry
DOIs
Publication statusAccepted/In press - Jun 27 2018

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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    Temido-Ferreira, M., Ferreira, D. G., Batalha, V. L., Marques-Morgado, I., Coelho, J. E., Pereira, P., Gomes, R., Pinto, A., Carvalho, S., Canas, P. M., Cuvelier, L., Buée-Scherrer, V., Faivre, E., Baqi, Y., Müller, C. E., Pimentel, J., Schiffmann, S. N., Buée, L., Bader, M., ... Lopes, L. V. (Accepted/In press). Age-related shift in LTD is dependent on neuronal adenosine A2A receptors interplay with mGluR5 and NMDA receptors. Molecular Psychiatry, 1-25. https://doi.org/10.1038/s41380-018-0110-9