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. Outeiro; David Blum; Rodrigo A. Cunha; Hélène Marie; Paula A. Pousinha; Luísa V. Lopes

doi:10.1038/s41380-018-0110-9

Age-related shift in LTD is dependent on neuronal adenosine A_2A 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^*

^*Corresponding author for this work

Chemistry

Research output: Contribution to journal › Article › peer-review

117 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 A_2A receptor (A_2AR) encoding gene—ADORA2A, and hippocampal volume in AD patients was recently described. In this study, we explore the synaptic function of A_2AR in age-related conditions. We report, for the first time, a significant overexpression of A_2AR in hippocampal neurons of aged humans, which is aggravated in AD patients. A similar profile of A_2AR 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 A_2AR blockade. This A_2AR/mGluR5/NMDAR interaction might prove a suitable alternative for regulating aberrant mGluR5/NMDAR signaling in AD without disrupting their constitutive activity.

Original language	English
Pages (from-to)	1876-1900
Number of pages	25
Journal	Molecular Psychiatry
Volume	25
Issue number	8
DOIs	https://doi.org/10.1038/s41380-018-0110-9
Publication status	Published - 2020

ASJC Scopus subject areas

Psychiatry and Mental health
Cellular and Molecular Neuroscience
Molecular Biology

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10.1038/s41380-018-0110-9

Cite this

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. (2020). Age-related shift in LTD is dependent on neuronal adenosine A_2A receptors interplay with mGluR5 and NMDA receptors. Molecular Psychiatry, 25(8), 1876-1900. https://doi.org/10.1038/s41380-018-0110-9

Temido-Ferreira, M, Ferreira, DG, Batalha, VL, Marques-Morgado, I, Coelho, JE, Pereira, P, Gomes, R, Pinto, A, Carvalho, S, Canas, PM, Cuvelier, L, Buée-Scherrer, V, Faivre, E, Baqi, Y, Müller, CE, Pimentel, J, Schiffmann, SN, Buée, L, Bader, M, Outeiro, TF, Blum, D, Cunha, RA, Marie, H, Pousinha, PA & Lopes, LV 2020, 'Age-related shift in LTD is dependent on neuronal adenosine A_2A receptors interplay with mGluR5 and NMDA receptors', Molecular Psychiatry, vol. 25, no. 8, pp. 1876-1900. https://doi.org/10.1038/s41380-018-0110-9

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AU - Temido-Ferreira, Mariana

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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.

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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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