Convergence of adenosine and GABA signaling for synapse stabilization during development

During development, neural circuit formation requires the stabilization of active gamma-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 A(2A) receptors (A(2A)Rs) stabilizes GABAergic synapses, only A(2A)R activation is sufficient. Both GABAAR- and A(2A)R-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 A(2A)Rs act as detectors of active GABAergic synapses releasing GABA, adenosine triphosphate, and adenosine to regulate their fate toward stabilization or elimination.