Convergence of adenosine and GABA signaling for synapse stabilization during development

Ferran Gomez-Castro, Stefania Zappettini, Jessica C Pressey, Carla G Silva, Marion Russeau, Nicolas Gervasi, Marta Figueiredo, Claire Montmasson, Marianne Renner, Paula M Canas, Francisco Q Gonçalves, Sofia Alçada-Morais, Eszter Szabó, Ricardo J Rodrigues, Paula Agostinho, Angelo R Tomé, Ghislaine Caillol, Olivier Thoumine, Xavier Nicol, Christophe LeterrierRafael Lujan, Shiva K Tyagarajan, Rodrigo A Cunha, Monique Esclapez, Christophe Bernard, Sabine Lévi

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

During development, neural circuit formation requires the stabilization of active g-aminobutyric acid- mediated (GABAergic) synapses and the elimination of inactive ones. Here, we demonstrate that, although the activation of postsynaptic GABA type A receptors (GABAARs) and adenosine A2A receptors (A2ARs) stabilizes GABAergic synapses, only A2AR activation is sufficient. Both GABAAR- and A2AR-dependent signaling pathways act synergistically to produce adenosine 3′,5′-monophosphate through the recruitment of the calcium-calmodulin-adenylyl cyclase pathway. Protein kinase A, thus activated, phosphorylates gephyrin on serine residue 303, which is required for GABAAR stabilization. Finally, the stabilization of pre- and postsynaptic GABAergic elements involves the interaction between gephyrin and the synaptogenic membrane protein Slitrk3. We propose that A2ARs act as detectors of active GABAergic synapses releasing GABA, adenosine triphosphate, and adenosine to regulate their fate toward stabilization or elimination.

Original languageEnglish
Article numbereabk2055
JournalScience
Volume374
Issue number6568
DOIs
Publication statusPublished - 2021
Externally publishedYes

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