INSERM UMR-S 1270, Sorbonne Université, Institut du Fer à Moulin, Paris, France.
Aix Marseille Université, INSERM, INS, Institut de Neurosciences des Systèmes, Marseille, France.
Science. 2021 Nov 5;374(6568):eabk2055. doi: 10.1126/science.abk2055.
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 (GABARs) and adenosine A receptors (ARs) stabilizes GABAergic synapses, only AR activation is sufficient. Both GABAR- and AR-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 GABAR stabilization. Finally, the stabilization of pre- and postsynaptic GABAergic elements involves the interaction between gephyrin and the synaptogenic membrane protein Slitrk3. We propose that ARs act as detectors of active GABAergic synapses releasing GABA, adenosine triphosphate, and adenosine to regulate their fate toward stabilization or elimination.
在发育过程中，神经回路的形成需要稳定活性 γ-氨基丁酸介导的（GABAergic）突触并消除非活性突触。在这里，我们证明，尽管突触后 GABA 型 A 受体（GABARs）和腺苷 A 受体（ARs）的激活稳定 GABAergic 突触，但只有 AR 的激活是足够的。GABAR 和 AR 依赖的信号通路通过募集钙-钙调蛋白-腺苷酸环化酶途径协同作用产生 3'，5'-单磷酸腺苷。由此激活的蛋白激酶 A 磷酸化 gephyrin 的丝氨酸残基 303，这是 GABAR 稳定所必需的。最后，前突触和后突触 GABAergic 元件的稳定涉及 gephyin 和突触发生膜蛋白 Slitrk3 之间的相互作用。我们提出，AR 作为释放 GABA、三磷酸腺苷和腺苷的活性 GABAergic 突触的检测器发挥作用，以调节它们向稳定或消除的命运。
