Convergence of adenosine and GABA signaling for synapse stabilization during development

Science. 2021 Nov 5;374(6568):eabk2055. doi: 10.1126/science.abk2055. Epub 2021 Nov 5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / metabolism*
  • Adenosine A2 Receptor Antagonists
  • Adenosine Triphosphate / metabolism
  • Animals
  • Calcium / metabolism
  • Cognition
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Hippocampus / growth & development*
  • Hippocampus / metabolism
  • Male
  • Membrane Proteins / metabolism
  • Mice
  • Nerve Tissue Proteins
  • Neurons / physiology*
  • Phosphorylation
  • Receptor, Adenosine A2A / genetics
  • Receptor, Adenosine A2A / metabolism*
  • Receptors, GABA-A / metabolism
  • Signal Transduction*
  • Synapses / physiology*
  • gamma-Aminobutyric Acid / metabolism*


  • Adenosine A2 Receptor Antagonists
  • Adora2a protein, mouse
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Receptor, Adenosine A2A
  • Receptors, GABA-A
  • gephyrin
  • gamma-Aminobutyric Acid
  • Adenosine Triphosphate
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Adenosine
  • Calcium