A Noelin-organized extracellular network of proteins required for constitutive and context-dependent anchoring of AMPA-receptors
Sami Boudkkazi, Jochen Schwenk, Naoki Nakaya, Aline Bréchet, Astrid Kollewe, Harumi Harada, Wolfgang Bildl, Ákos Kulik, Lijin Dong, Afia Sultana, Gerd Zolles, Uwe Schulte, Stanislav I. Tomarev, Bernd Fakler
Abstract
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.