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. 2018 Jun 27.
doi: 10.1038/s41380-018-0110-9. Online ahead of print.

Age-related Shift in LTD Is Dependent on Neuronal Adenosine A 2A Receptors Interplay With mGluR5 and NMDA Receptors

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Age-related Shift in LTD Is Dependent on Neuronal Adenosine A 2A Receptors Interplay With mGluR5 and NMDA Receptors

Mariana Temido-Ferreira et al. Mol Psychiatry. .

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.

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