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The intracerebroventricular (icv) injection of amyloid peptides (Aβ) models Alzheimer's disease (AD) in mice, as typified by the onset within 15 days of deficits of memory and of hippocampal long-term potentiation (LTP) that are prevented by the blockade of adenosine A 2A receptors (A 2A R). Since A 2A R overfunction is sufficient to trigger memory deficits, we tested if A 2A R were upregulated in hippocampal synapses before the onset of memory deficits to support the hypothesis that A 2A R overfunction could be a trigger of AD. Six to eight days after Aβ-icv injection, mice displayed no alterations of hippocampal dependent memory; however, they presented an increased excitability of hippocampal synapses, a slight increase in LTP magnitude in Schaffer fiber-CA1 pyramid synapses and an increased density of A 2A R in hippocampal synapses. A 2A R blockade with SCH58261 (50 nM) normalized excitability and LTP in hippocampal slices from mice sacrificed 7-8 days after Aβ-icv injection. Fifteen days after Aβ-icv injection, mice displayed evident deficits of hippocampal-dependent memory deterioration, with reduced hippocampal CA1 LTP but no hyperexcitability and a sustained increase in synaptic A 2A R, which blockade restored LTP magnitude. This shows that the upregulation of synaptic A 2A R precedes the onset of deterioration of memory and of hippocampal synaptic plasticity, supporting the hypothesis that the overfunction of synaptic A 2A R could be a trigger of memory deterioration in AD.