# Neurophysiological In Vitro Model of Amyloid-β-Induced Deficits of Hippocampal LTP Involving Neuronal Adenosine A2A Receptor Dysfunction Through CD73

## TL;DR

This study explores how amyloid-beta affects brain cell communication by focusing on adenosine receptors and CD73 in mouse hippocampal slices.

## Contribution

The paper reveals a novel mechanism linking Aβ-induced synaptic dysfunction to adenosine A2A receptor activity mediated by CD73.

## Key findings

- Acute Aβ exposure impairs synaptic plasticity without affecting basal transmission.
- Extracellular adenosine is essential for Aβ effects, with A2AR mediating LTP deficits.
- CD73 inhibition confirms A2AR overfunction in Aβ-induced synaptic dysfunction.

## Abstract

Amyloid-β peptides (Aβ) are considered a main culprit of Alzheimer’s disease (AD), leading to synaptic dysfunction and memory deficits. Although studies in animal models of AD converge to show alterations of synaptic plasticity, namely of long-term potentiation (LTP), the mechanisms through which Aβ affects synaptic function remain to be unveiled. In this study, we established experimental conditions showing that the acute exposure of mouse hippocampal slices to optimized concentrations of Aβ impaired short-term (PPF-paired-pulse facilitation) and long-term (LTP-long-term potentiation) plasticity without altering basal synaptic transmission. We observed that the elimination of extracellular adenosine with adenosine deaminase abrogated the impact of Aβ on synaptic plasticity, showing a mandatory involvement of extracellular adenosine in the neurophysiological effects of Aβ. Additionally, inhibiting adenosine receptor function with caffeine, as well as selectively blocking adenosine A1 receptors (A1R) with DPCPX, or adenosine A2A receptor (A2AR) with either an antagonist SCH58261 or through knocking out A2AR, demonstrated that acute Aβ modified mouse hippocampal PPF via A1R and LTP through A2AR. Furthermore, the use of slices from mice bearing forebrain-neuron A2AR deletion, along with the application of α,β-methylene ADP, a CD73 inhibitor, confirmed that the neurophysiological actions of Aβ on hippocampal LTP occur selectively through the overfunction of neuronal A2AR via CD73-mediated formation of extracellular adenosine. Overall, the exploitation of a neurophysiological model of early AD, based on the acute administration of Aβ to hippocampal slices, confirmed the critical involvement of adenosine signaling in the impact of Aβ on synaptic plasticity.