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

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.

Stress early in life leads to cognitive impairments, reduced numbers of CA3 neurons and altered maternal behavior in adult female mice

“…Additionally, CA3‐CA3 connections play an important role in the initial storage of memory . Disruptions of synaptic transmission in CA3‐CA3 lead to deficits in one‐trial learning and one‐trial memory . Our data on reduced neuronal populations in CA3 in adult F0 females probably are suggestive of disturbed plasticity in this hippocampal region, possibly owing to a reduction in the number of synapses or in dendritic arborization or other changes leading to less effective signal transmission, thereby in turn causing changes in the memory processes.…”

Region‐specific control of microglia by adenosine A2A receptors: uncoupling anxiety and associated cognitive deficits in female rats

“…Several studies have previously shown that A 2A R blockade prevents memory deficits associated with chronic stress or depression (Batalha et al, ; Cunha et al, ; Kaster et al, ; Machado et al, ). These studies focused on the relation between synaptic dysfunction and memory deterioration and have shown that neuronal A 2A R were both necessary and sufficient to trigger memory deficits (Li et al, ; Pagnussat et al, ; Viana da Silva et al, ). Although the blockade of A 2A R is globally accepted as a cognitive enhancer and anxiolytic, in animal models of disease, the majority of the studies were performed in males or the gender was not specified.…”

“…Since patients with anxiety disorders commonly display cognitive impairment (Kendler et al, ; Tanokashira et al, ) and A 2A R blockade prevents cognitive deficits (Batalha et al, ; Cunha et al, ; Dall'Igna et al, ; Kaster et al, ; Li et al, ; Prediger et al, ; Viana da Silva et al, ), we now investigated if A 2A R blockade recovers cognition in females with anxiety resistant to A 2A R antagonism. We further assessed if A 2A R in the dorsal hippocampus (dHIP) and in the mPFC differently control microglia morphologic remodeling in these two brain regions, which process anxiety and cognitive performance.…”

Age‑dependent concomitant changes in synaptic function and GABAergic pathway in the APP/PS1 mouse model

“…memory formation (Shors and Matzel 1997, Malenka and Nicoll 1999, Bliim et al 2016. Furthermore, the fact that LTP deficit is a common theme observed in AD mouse models strengthens the link between LTP and memory deficits observed in both clinical and/or preclinical research (Gengler et al 2010, Sheng et al 2012, Webster et al 2014, Viana da Silva et al 2016). …”