Convergence of adenosine and GABA signaling for synapse stabilization during development

authors

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

abstract

During development, neural circuit formation requires the stabilization of active γ-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.

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