Optogenetic control of excitatory post-synaptic differentiation through neuroligin-1 tyrosine phosphorylation

Neuroligins (Nlgs) are adhesion proteins mediating trans-synaptic contacts in neurons. However, conflicting results around their role in synaptic differentiation arise from the various techniques used to manipulate Nlg expression. Orthogonally to these approaches, we triggered here the phosphorylation of endogenous Nlg1 in CA1 hippocampal neurons using a photoactivatable tyrosine kinase receptor (optoFGFR1). Light stimulation for 24 h selectively increased dendritic spine density and AMPA receptor-mediated EPSCs in wild-type neurons, but not in Nlg1 knock-out neurons or when endogenous Nlg1 was replaced by a non-phosphorylatable mutant (Y782F). Moreover, light stimulation of optoFGFR1 partially occluded LTP. Combined with computer simulations, our data support a model by which Nlg1 tyrosine phosphorylation promotes the assembly of an excitatory post-synaptic scaffold that captures surface AMPA receptors. This optogenetic strategy thus highlights the impact of Nlg1 intracellular signaling in synaptic differentiation and potentiation, while enabling an acute control of these mechanisms. Impact Statement Orthogonal to the traditional paradigms used to manipulate neuroligin expression level, the optogenetic trigger of tyrosine phosphorylation supports a strong role of endogenous neuroligin-1 in excitatory synaptic differentiation and potentiation.