Early synaptic deficits in the APP/PS1 mouse model of Alzheimer's disease involve neuronal adenosine A(2A) receptors

Synaptic plasticity in the autoassociative network of recurrent connections among hippocampal CA3 pyramidal cells is thought to enable the storage of episodic memory. Impaired episodic memory is an early manifestation of cognitive deficits in Alzheimer's 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(2A) receptors (A(2A)R) rather than by dysregulation of NMDAR signalling or altered dendritic spine morphology. Neutralization of A(2A)R by acute pharmacological inhibition, or downregulation driven by shRNA interference in a single postsynaptic neuron restore associative CA3 LTP. Accordingly, treatment with A(2A)R antagonists reverts one-trial memory deficits. These results provide mechanistic support to encourage testing the therapeutic efficacy of A(2A)R antagonists in early AD patients.