Neurexin-Neuroligin Adhesions Capture Surface-Diffusing AMPA Receptors through PSD-95 Scaffolds

• DOI: 10.1523/jneurosci.6439-10.2011
• Publication Date: 2011-09-21T16:50:18Z
• Authors: Magali Mondin; Virginie Labrousse; Eric Hosy; Martin Heine; Béatrice Tessier; Florian Levet; Christel Poujol; Christophe Blanchet; Daniel Choquet; Olivier Thoumine
• Keywords: Male; Mice, Knockout; 0303 health sciences; Patch-Clamp Techniques; Cell Adhesion Molecules, Neuronal; Calcium-Binding Proteins; Primary Cell Culture; Membrane Proteins; Transfection; Hippocampus; Synaptic Transmission; Membrane Potentials; Rats; Mice; 03 medical and health sciences; Mutation; Animals; Female; Receptors, AMPA; Disks Large Homolog 4 Protein; Guanylate Kinases; Neural Cell Adhesion Molecules

The mechanisms governing the recruitment of functional glutamate receptors at nascent excitatory postsynapses following initial axon-dendrite contact remain unclear. We examined here the ability of neurexin/neuroligin adhesions to mobilize AMPA-type glutamate receptors (AMPARs) at postsynapses through a diffusion/trap process involving the scaffold molecule PSD-95. Using single nanoparticle tracking in primary rat and mouse hippocampal neurons overexpressing or lacking neuroligin-1 (Nlg1), a striking inverse correlation was found between AMPAR diffusion and Nlg1 expression level. The use of Nlg1 mutants and inhibitory RNAs against PSD-95 demonstrated that this effect depended on intact Nlg1/PSD-95 interactions. Furthermore, functional AMPARs were recruited within 1 h at nascent Nlg1/PSD-95 clusters assembled by neurexin-1β multimers, a process requiring AMPAR membrane diffusion. Triggering novel neurexin/neuroligin adhesions also caused a depletion of PSD-95 from native synapses and a drop in AMPAR miniature EPSCs, indicating a competitive mechanism. Finally, both AMPAR level at synapses and AMPAR-dependent synaptic transmission were diminished in hippocampal slices from newborn Nlg1 knock-out mice, confirming an important role of Nlg1 in driving AMPARs to nascent synapses. Together, these data reveal a mechanism by which membrane-diffusing AMPARs can be rapidly trapped at PSD-95 scaffolds assembled at nascent neurexin/neuroligin adhesions, in competition with existing synapses.