Early Synaptic Deficits in the APP/PS1 Mouse Model of Alzheimer's Disease Involve Neuronal Adenosine A2A Receptors

Overview

Journal Nat Commun

Specialty Biology

Date 2016 Jun 18

PMID 27312972

Citations 115

Authors

Silvia Viana da Silva

Matthias Georg Haberl

Pei Zhang

Philipp Bethge

Cristina Lemos

Nelio Goncalves

Adam Gorlewicz

Meryl Malezieux

Francisco Q Goncalves

Noelle Grosjean

Christophe Blanchet

Andreas Frick

U Valentin Nagerl

Rodrigo A Cunha

Christophe Mulle

Affiliations

Soon will be listed here.

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.

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