The paradoxical role of adenosine A2A receptor in the control of synapse stabilization and elimination

Adenosine acts as a fine regulator of synaptic plasticity in the adult brain. We showed a key role for the adenosine A2A receptor (A2AR) in the stabilization of nascent active GABAergic synapses during brain development (Gomez-Castro et al., Science 374 2021). Our data indicate that this regulation extends to glutamatergic synapses and involve neuroglial interactions. The suppression of neuronal A2AR with a shRNA approach in mixed neuron-glia cultures led to the loss of ~30% of glutamatergic synapses. Puzzlingly, activating A2AR in these cultures with a selective agonist (CGS21680) also led to synapse loss, an effect blocked upon depletion of microglia or upon blockade of the complement system. qRT-PCR on purified microglia and immunohistochemistry on hippocampal slices led to the conclusion that these cells do not express A2AR during or after synaptogenesis, in contrast to neurons and astrocytes for which a peak of expression coincides with the synaptogenesis period. Pilot experiments report that neuronal A2AR stabilizes glutamatergic synapses through AC/cAMP/PKA pathway while the astrocytic A2AR controls synaptic pruning presumably by activating microglia. Future work will elucidate the targets of PKA in neurons that underlie synapse stabilization and the neuroglial mechanisms involved in synapse pruning. Altogether, our data indicate a central and complex role for neuro-glial A2ARs in glutamatergic synaptogenesis. The appropriate number of glutamatergic synapses formed during development would thus depend on a balance between the signaling activated in neurons or astrocytes.