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Nature Research, Nature Communications, 1(7), 2016

DOI: 10.1038/ncomms11915

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Early synaptic deficits in the APP/PS1 mouse model of Alzheimer’s disease involve neuronal adenosine A2A receptors

Journal article published in 2016 by Silvia Viana da Silva, Matthias Georg Haberl, Pei Zhang, Philipp Bethge, Cristina Lemos, Nélio Gonçalves ORCID, Adam Gorlewicz, Meryl Malezieux, Francisco Q. Gonçalves ORCID, Noëlle Grosjean, Christophe Blanchet, Andreas Frick, U. Valentin Nägerl, Rodrigo A. Cunha ORCID, Christophe Mulle
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

AbstractSynaptic 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 A2A receptors (A2AR) rather than by dysregulation of NMDAR signalling or altered dendritic spine morphology. Neutralization of A2AR by acute pharmacological inhibition, or downregulation driven by shRNA interference in a single postsynaptic neuron restore associative CA3 LTP. Accordingly, treatment with A2AR antagonists reverts one-trial memory deficits. These results provide mechanistic support to encourage testing the therapeutic efficacy of A2AR antagonists in early AD patients.