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

Silvia Viana da Silva, Matthias Georg Haberl, Pei Zhang, Philipp Bethge, Cristina Lemos, Nélio Gonçalves, Adam Gorlewicz, Meryl Malezieux, Francisco Q. Gonçalves, Noëlle Grosjean, Christophe Blanchet, Andreas Frick, U Valentin Nägerl, Rodrigo A. Cunha and Christophe Mulle ()
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Silvia Viana da Silva: Interdisciplinary Institute for Neuroscience, University of Bordeaux
Matthias Georg Haberl: University of Bordeaux, Neurocentre Magendie, INSERM U862, F-33000 Bordeaux, France
Pei Zhang: Interdisciplinary Institute for Neuroscience, University of Bordeaux
Philipp Bethge: Interdisciplinary Institute for Neuroscience, University of Bordeaux
Cristina Lemos: CNC-Center for Neuroscience and Cell Biology, University of Coimbra
Nélio Gonçalves: CNC-Center for Neuroscience and Cell Biology, University of Coimbra
Adam Gorlewicz: Interdisciplinary Institute for Neuroscience, University of Bordeaux
Meryl Malezieux: Interdisciplinary Institute for Neuroscience, University of Bordeaux
Francisco Q. Gonçalves: CNC-Center for Neuroscience and Cell Biology, University of Coimbra
Noëlle Grosjean: Interdisciplinary Institute for Neuroscience, University of Bordeaux
Christophe Blanchet: Interdisciplinary Institute for Neuroscience, University of Bordeaux
Andreas Frick: University of Bordeaux, Neurocentre Magendie, INSERM U862, F-33000 Bordeaux, France
U Valentin Nägerl: Interdisciplinary Institute for Neuroscience, University of Bordeaux
Rodrigo A. Cunha: CNC-Center for Neuroscience and Cell Biology, University of Coimbra
Christophe Mulle: Interdisciplinary Institute for Neuroscience, University of Bordeaux

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: Abstract 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 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.

Date: 2016
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DOI: 10.1038/ncomms11915

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