PKA-mediated phosphorylation of Neuroligin-2 regulates its cell surface expression and synaptic stabilisation

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 stabilises GABA-A receptors (GABAARs) in the postsynaptic domain. Dynamic regulation of synaptic GABAAR concentration is crucial for inhibitory neurotransmission efficacy. Changes in synaptic levels of NL2 contribute to regulating GABAAR synaptic concentration, however the mechanisms that control NL2 synaptic stabilisation are mostly unknown. Here, by combining biochemistry, imaging, single particle tracking and electrophysiology, we identify a key role for cAMP-dependent protein kinase (PKA) in synaptic stabilisation of NL2. We show that PKA-mediated phosphorylation of NL2 at S714 causes its dispersal from the synapse and reduces NL2 surface levels, leading to a loss of synaptic GABAARs. Conversely, enhanced stability of NL2 at synapses through abolishing phosphorylation leads to increased inhibitory signalling. Thus, PKA plays a key role in regulating NL2 function and synaptic inhibition.