Anales RANF

S15-04 A 2A R SIGNALLING REGULATES SYNAPTOGENESIS IN THE DEVELOPING BRAIN Sabine Lévi INSERM UMR-S 839, Université Pierre et Marie Curie, 75005, Paris, France. In the adult brain, adenosine, a degradation product of ATP, controls neurotransmitter release and synaptic plasticity through G protein coupled A 1 and A 2A receptors. However, its role in development remains to be elucidated. Here, we addressed the role of A 2A R-mediated signalling during GABAergic synaptogenesis in the hippocampus. We found that A 2A R expression peaked during the period of synaptogenesis in the hippocampus in vitro and in vivo . This developmental expression of A 2A Rs was correlated with a role of A 2A Rs in the stabilization of nascent GABA synapses during synaptogenesis. We demonstrated that the A 2A R-mediated synapse stabilization is a cell autonomous process that requires A 2A R activation in the postsynaptic cell. We then characterized the molecular mechanism downstream A 2A Rs. We identified the Adenylyl cyclase/cAMP/Protein Kinase A (PKA) signalling cascade as the main molecular pathway and the postsynaptic scaffolding molecule gephyrin as a main target of PKA activation. Finally, we will provide evidences that the deleterious consequences of in utero and post-natal brain exposure to caffeine (Sci Transl Med. 2013; 5(197), an antagonist of A1 and A2A receptors, are primarily due to A 2A R-dependent alterations in synaptogenesis. Our findings allow to propose that A 2A Rs act as coincidence detectors to stabilize newly formed GABAergic synapses during synaptogenesis and provide a better understanding of the pathological mechanisms engaged upon early-life exposure to caffeine.