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

Silvia Viana Da Silva,Pei Zhang,Christophe Mulle,Matthias Georg Haberl,Francisco Q Gonçalves,Christophe Blanchet,Andreas Frick,Nélio Gonçalves,Cristina Lemos,Adam Gorlewicz,Meryl Malezieux,Noëlle Grosjean,U Valentin Nägerl,Philipp Bethge,Rodrigo A Cunha

doi:10.1038/ncomms11915

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.

Highlights

Synaptic plasticity in the autoassociative network of recurrent connections among hippocampal CA3 pyramidal cells is thought to enable the storage of episodic memory
The average amplitude of mEPSCs was significantly decreased in APP/PS1 compared with wild-type mice, whereas mEPSC frequency, measured by the inter event interval (IEI), was only minimally affected
We further found that the paired-pulse ratio (PPR) of A/C synaptic responses was not different between APP/PS1 (1.9±0.1) and wt mice (1.8±0.1), arguing against presynaptic alterations (Fig. 1a–c)

Summary

Introduction

Synaptic plasticity in the autoassociative network of recurrent connections among hippocampal CA3 pyramidal cells is thought to enable the storage of episodic memory. 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. The autoassociative network of recurrent connections among CA3 pyramidal cells (PCs) is thought to enable the storage of episodic memories through synaptic plasticity of these associative/commissural (A/C) inputs[4,5]. We provide evidence for early synaptic dysfunction in CA3 PCs in a mouse model of AD, and we explore the implication of NMDAR and A2AR

Methods

Results

Conclusion