Halff_2022_Sci.Signal_15_eabg2505

The trans-synaptic adhesion molecule neuroligin-2 (NL2) is essential for the development and function of inhibitory synapses. NL2 recruits the postsynaptic scaffold protein gephyrin, which, in turn, stabilizes gamma-aminobutyric acid type A receptors (GABA(A)Rs) in the postsynaptic domain. Thus, the amount of NL2 at the synapse can control synaptic GABA(A)R concentration to tune inhibitory neurotransmission efficacy. Here, using biochemistry, imaging, single-particle tracking, and electrophysiology, we uncovered a key role for cAMP-dependent protein kinase (PKA) in the synaptic stabilization of NL2. We found that PKA-mediated phosphorylation of NL2 at Ser(714) caused its dispersal from the synapse and reduced NL2 surface amounts, leading to a loss of synaptic GABA(A)Rs. Conversely, enhancing the stability of NL2 at synapses by abolishing PKA-mediated phosphorylation led to increased inhibitory signaling. Thus, PKA plays a key role in regulating NL2 function and GABA-mediated synaptic inhibition.