cAMP-EPAC-Dependent Regulation of Gephyrin Phosphorylation and GABA(A)R Trapping at Inhibitory Synapses

GABA(A) and glycine receptors are thought to compete for gephyrin-binding sites at mixed inhibitory synapses. Changes in the occupancy of one receptor type are therefore expected to have opposite effects on the clustering of the other receptors. This does not explain, however, whether different receptors can be regulated independently from one another. Here we show that cAMP-dependent signaling reduces gephyrin phosphorylation at residue S270 in spinal cord neurons. Although no ultrastructural changes of the synaptic scaffold were detected using super-resolution imaging, gephyrin de-phosphorylation was associated with a selective increase in GABA(A)R diffusion and the loss of the receptors from synapses. As opposed to the PKA-dependent dispersal of α3-containing GlyRs, the regulation of gephyrin phosphorylation and GABA(A)R dynamics acts via non-canonical EPAC signaling. Subtype-specific changes in receptor mobility can thus differentially contribute to changes in inhibitory synaptic strength, such as the disinhibition of spinal cord neurons during inflammatory processes.