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Age-related shift in LTD is dependent on neuronal adenosine A_2A receptors interplay with mGluR5 and NMDA receptors

Lookup NU author(s): Professor Tiago OuteiroORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2018 The Author(s). 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.

Publication metadata

Author(s): Temido-Ferreira M, Ferreira DG, Batalha VL, Marques-Morgado I, Coelho JE, Pereira P, Gomes R, Pinto A, Carvalho S, Canas PM, Cuvelier L, Buee-Scherrer V, Faivre E, Baqi Y, Muller CE, Pimentel J, Schiffmann SN, Buee L, Bader M, Outeiro TF, Blum D, Cunha RA, Marie H, Pousinha PA, Lopes LV

Publication type: Article

Publication status: Published

Journal: Molecular Psychiatry

Year: 2020

Volume: 25

Pages: 1876-1900

Print publication date: 01/08/2020

Online publication date: 27/06/2018

Acceptance date: 14/05/2018

Date deposited: 09/07/2018

ISSN (print): 1359-4184

ISSN (electronic): 1476-5578

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/s41380-018-0110-9

DOI: 10.1038/s41380-018-0110-9

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