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

Neuron. 2023 Aug 16;111(16):2544-2556.e9. 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.

Keywords: AMPA-receptor; excitatory neurotransmission; extracellular matrix; long-term potentiation; mass spectrometry; protein-protein interaction; proteomics; secreteted proteins; synaptic plasticity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Intramural

MeSH terms

  • Biological Transport
  • Brain*
  • Cell Membrane
  • Membrane Proteins* / genetics
  • Receptors, AMPA
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid


  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
  • Membrane Proteins
  • Receptors, AMPA