Early synaptic deficits in the APP/PS1 mouse model of Alzheimer's disease involve neuronal adenosine A2A 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 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.
Interdisciplinary Institute for Neuroscience, University of Bordeaux, CNRS UMR 5297, F-33000 Bordeaux, France.|BEB PhD program CNC Coimbra, 3004-517 Coimbra, Portugal.
Silvia
S
Viana da Silva
University of Bordeaux, Neurocentre Magendie, INSERM U862, F-33000 Bordeaux, France.
Matthias Georg
MG
Haberl
Interdisciplinary Institute for Neuroscience, University of Bordeaux, CNRS UMR 5297, F-33000 Bordeaux, France.
Pei
P
Zhang
Interdisciplinary Institute for Neuroscience, University of Bordeaux, CNRS UMR 5297, F-33000 Bordeaux, France.
Philipp
P
Bethge
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
Cristina
C
Lemos
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
Nélio
N
Gonçalves
Interdisciplinary Institute for Neuroscience, University of Bordeaux, CNRS UMR 5297, F-33000 Bordeaux, France.
Adam
A
Gorlewicz
Interdisciplinary Institute for Neuroscience, University of Bordeaux, CNRS UMR 5297, F-33000 Bordeaux, France.
Meryl
M
Malezieux
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
Francisco Q
FQ
Gonçalves
Interdisciplinary Institute for Neuroscience, University of Bordeaux, CNRS UMR 5297, F-33000 Bordeaux, France.
Noëlle
N
Grosjean
Interdisciplinary Institute for Neuroscience, University of Bordeaux, CNRS UMR 5297, F-33000 Bordeaux, France.
Christophe
C
Blanchet
University of Bordeaux, Neurocentre Magendie, INSERM U862, F-33000 Bordeaux, France.
Andreas
A
Frick
Interdisciplinary Institute for Neuroscience, University of Bordeaux, CNRS UMR 5297, F-33000 Bordeaux, France.
U Valentin
UV
Nägerl
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.|Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal.
Rodrigo A
0000-0003-2550-6422
RA
Cunha
Interdisciplinary Institute for Neuroscience, University of Bordeaux, CNRS UMR 5297, F-33000 Bordeaux, France.
Christophe
C
Mulle
D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology*; D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D056654:CA3 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D017774:Long-Term Potentiation; D061212:Memory, Episodic; D051379:Mice; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000494:pharmacology*; D053764:Presenilin-1 / Q000235:genetics* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000235:genetics* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology
C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D058917:Adenosine A2 Receptor Antagonists; D016564:Amyloid beta-Protein Precursor; D018696:Neuroprotective Agents; D053764:Presenilin-1; D011743:Pyrimidines; D034741:RNA, Small Interfering; D043705:Receptor, Adenosine A2A; D016194:Receptors, N-Methyl-D-Aspartate; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; C580804:presenilin 1, mouse