Early synaptic deficits in the APP/PS1 mouse model of Alzheimer’s disease involve neuronal adenosine A2A receptors.
Nat Comms. 2016-06-17; 7: 11915
DOI: 10.1038/ncomms11915
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1. Nat Commun. 2016 Jun 17;7:11915. doi: 10.1038/ncomms11915.
Early synaptic deficits in the APP/PS1 mouse model of Alzheimer’s disease involve
neuronal adenosine A2A receptors.
Viana da Silva S(1)(2), Haberl MG(3), Zhang P(1), Bethge P(1), Lemos C(4),
Gonçalves N(4), Gorlewicz A(1), Malezieux M(1), Gonçalves FQ(4), Grosjean N(1),
Blanchet C(1), Frick A(3), Nägerl UV(1), Cunha RA(4)(5), Mulle C(1).
Author information:
(1)Interdisciplinary Institute for Neuroscience, University of Bordeaux, CNRS UMR
5297, F-33000 Bordeaux, France.
(2)BEB PhD program CNC Coimbra, 3004-517 Coimbra, Portugal.
(3)University of Bordeaux, Neurocentre Magendie, INSERM U862, F-33000 Bordeaux,
France.
(4)CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517
Coimbra, Portugal.
(5)Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal.
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.
DOI: 10.1038/ncomms11915
PMCID: PMC4915032
PMID: 27312972