Age-related shift in LTD is dependent on neuronal adenosine A 2A receptors interplay with mGluR5 and NMDA receptors

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 2A R) encoding gene— ADORA2A , and hippocampal volume in AD patients was recently described. In this study, we explore the synaptic function of A 2A R in age-related conditions. We report, for the first time, a significant overexpression of A 2A R in hippocampal neurons of aged humans, which is aggravated in AD patients. A similar profile of A 2A R 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 Ca 2+ influx. We confirmed the same plasticity shift in memory-impaired aged rats and APP/PS1 mice modeling AD, which was rescued upon A 2A R blockade. This A 2A R/mGluR5/NMDAR interaction might prove a suitable alternative for regulating aberrant mGluR5/NMDAR signaling in AD without disrupting their constitutive activity.