Adenosine A 2A Receptor Up-Regulation Pre-Dates Deficits of Synaptic Plasticity and of Memory in Mice Exposed to Aβ 1-42 to Model Early Alzheimer's Disease.

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.