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

Reduction of A 2A receptor expression is one of the earliest events occurring in both Huntington's disease (HD) patients and mice overexpressing the N-terminal part of mutated huntingtin. Interestingly, increased activity of A 2A receptors has been found in striatal cells prone to degenerate in experimental models of this neurodegenerative disease. However, the role of A 2A receptors in the pathogenesis of HD remains obscure. In the present study, using A 2A Ϫ/Ϫ mice and pharmacological compounds in rat, we demonstrate that striatal neurodegeneration induced by the mitochondrial toxin 3-nitropropionic acid (3NP) is regulated by A 2A receptors. Our results show that the striatal outcome induced by 3NP depends on a balance between the deleterious activity of presynaptic A 2A receptors and the protective activity of postsynaptic A 2A receptors. Moreover, microdialysis data demonstrate that this balance is anatomically determined, because the A 2A presynaptic control on striatal glutamate release is absent within the posterior striatum. Therefore, because blockade of A 2A receptors has differential effects on striatal cell death in vivo depending on its ability to modulate presynaptic over postsynaptic receptor activity, therapeutic use of A 2A antagonists in Huntington's as well as in other neurodegenerative diseases could exhibit undesirable biphasic neuroprotective-neurotoxic effects.

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