Aims

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. We now explored the role of A2AR in hippocampal function in age-related conditions.

Methods

We showed a significant upsurge of A2AR in hippocampal neurons of aged humans, a phenotype aggravated in AD patients. Increased expression of A2AR driven by the CaMKII promoter selectively in rat forebrain neurons was sufficient to mimic aging-like memory impairments and to uncover an LTD-to-LTP shift in the hippocampus.

Results

We report a significant overexpression of A2AR in hippocampal neurons of aged humans, which is aggravated in AD patients. A similar profile of A2AR overexpression in young rats was sufficient to drive age-like memory impairments and to uncover a LTD-to-LTP shift.

This shift was due to an increased NMDA receptor gating and associated to increased Ca2+ influx. We identified the mGluR5-NMDAR interplay as key player in the observed A2AR-induced synaptic dysfunction. Importantly, the same LTD-to-LTP shift was observed in memory-impaired aged rats and APP/PS1 mice modeling AD, a phenotype rescued upon A2AR blockade.

Conclusions

Due to the aberrant A2AR signaling in pathological conditions, their blockade is particularly relevant for long-term therapies, since the alternative option of targeting directly either mGluR5 or NMDAR interferes with basal neuronal function and memory, as these proteins are crucial components of the postsynaptic density.