Increased ATP release and CD73-mediated adenosine A2A receptor activation mediate convulsion-associated neuronal damage and hippocampal dysfunction

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(2A)R). Convulsive activity leads to increased ATP release, with the resulting morphological alterations being eliminated by A(2A)R blockade. However, it is not known if upon convulsions there is a CD73-mediated coupling between ATP release and A(2A)R overactivation, causing neurodegeneration. We now show that kainate-induced convulsions trigger a parallel increase of ATP release and of CD73 and A(2A)R 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(2A)R 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.

Automated summary

The study demonstrates that ATP release, CD73, and A(2A)R density increase upon convulsive activity, playing a key role in neurodegeneration. Genetic deletion of CD73 attenuates neuronal degeneration but has no impact on astrocytic modifications. Furthermore, knocking out CD73 eliminated the deterioration of long-term potentiation and memory performance caused by convulsions.