Increased ATP release and CD73-mediated adenosine A_2A receptor activation mediate convulsion-associated neuronal damage and hippocampal dysfunction

Highlights

• Convulsions lead to a sustained increase of ATP release from nerve terminals and astrocytes.

• Convulsions upregulate synaptic and astrocytic CD73 and adenosine A_2A receptors.

• CD73 knockout prevents convulsions-induced neurodegeneration and memory deficits.

• ATP-CD73-A_2A receptor overfunction is a new pathway responsible for neuronal damage.

Abstract

Extracellular ATP is a danger signal to the brain and contributes to neurodegeneration in animal models of Alzheimer's disease through its extracellular catabolism by CD73 to generate adenosine, bolstering the activation of adenosine A_2A receptors (A_2AR). Convulsive activity leads to increased ATP release, with the resulting morphological alterations being eliminated by A_2AR blockade. However, it is not known if upon convulsions there is a CD73-mediated coupling between ATP release and A_2AR overactivation, causing neurodegeneration. We now show that kainate-induced convulsions trigger a parallel increase of ATP release and of CD73 and A_2AR densities in synapses and astrocytes of the mouse hippocampus. Notably, the genetic deletion of CD73 attenuates neuronal degeneration but has no impact on astrocytic modifications in the hippocampus upon kainate-induced convulsions. Furthermore, kainate-induced convulsions cause a parallel deterioration of hippocampal long-term potentiation (LTP) and hippocampal-dependent memory performance, which is eliminated by knocking out CD73. This demonstrates the key role of the ATP release/CD73/A_2AR pathway to selectively control synaptic dysfunction and neurodegeneration following an acute brain insult, paving the way to consider CD73 as a new therapeutic target to prevent neuronal damage upon acute brain damage.