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Impaired episodic memory is an early manifestation of cognitive deficits in Alzheimer\u2019s disease (AD). In the APP\/PS1 mouse model of AD amyloidosis, we show that associative long-term synaptic potentiation (LTP) is abolished in CA3 pyramidal cells at an early stage. This is caused by activation of upregulated neuronal adenosine A<jats:sub>2A<\/jats:sub> receptors (A<jats:sub>2A<\/jats:sub>R) rather than by dysregulation of NMDAR signalling or altered dendritic spine morphology. Neutralization of A<jats:sub>2A<\/jats:sub>R by acute pharmacological inhibition, or downregulation driven by shRNA interference in a single postsynaptic neuron restore associative CA3 LTP. Accordingly, treatment with A<jats:sub>2A<\/jats:sub>R antagonists reverts one-trial memory deficits. 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