A Noelin-organized extracellular network of proteins required for constitutive and context-dependent anchoring of AMPA-receptors

• Published in: Neuron (Cambridge, Mass.) Mass.), 2023-08, Vol.111 (16), p.2544-2556.e9
• Main Authors: Boudkkazi, Sami, Schwenk, Jochen, Nakaya, Naoki, Brechet, Aline, Kollewe, Astrid, Harada, Harumi, Bildl, Wolfgang, Kulik, Akos, Dong, Lijin, Sultana, Afia, Zolles, Gerd, Schulte, Uwe, Tomarev, Stanislav, Fakler, Bernd
• Format: Article
• Language: English
• Subjects: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Biological Transport; Brain; Cell Membrane; Membrane Proteins - genetics; Receptors, AMPA
• ISSN: 0896-6273; 1097-4199; 1097-4199
• DOI: 10.1016/j.neuron.2023.07.013

Information processing and storage in the brain rely on AMPA-receptors (AMPARs) and their context-dependent dynamics in synapses and extra-synaptic sites. We found that distribution and dynamics of AMPARs in the plasma membrane are controlled by Noelins, a three-member family of conserved secreted proteins expressed throughout the brain in a cell-type-specific manner. Noelin tetramers tightly assemble with the extracellular domains of AMPARs and interconnect them in a network-like configuration with a variety of secreted and membrane-anchored proteins including Neurexin1, Neuritin1, and Seizure 6-like. Knock out of Noelins1-3 profoundly reduced AMPARs in synapses onto excitatory and inhibitory (inter)neurons, decreased their density and clustering in dendrites, and abolished activity-dependent synaptic plasticity. Our results uncover an endogenous mechanism for extracellular anchoring of AMPARs and establish Noelin-organized networks as versatile determinants of constitutive and context-dependent neurotransmission.