LGI1-ADAM22-MAGUK configures transsynaptic nanoalignment for synaptic transmission and epilepsy prevention

Proc Natl Acad Sci U S A. 2021 Jan 19;118(3):e2022580118. doi: 10.1073/pnas.2022580118.


Physiological functioning and homeostasis of the brain rely on finely tuned synaptic transmission, which involves nanoscale alignment between presynaptic neurotransmitter-release machinery and postsynaptic receptors. However, the molecular identity and physiological significance of transsynaptic nanoalignment remain incompletely understood. Here, we report that epilepsy gene products, a secreted protein LGI1 and its receptor ADAM22, govern transsynaptic nanoalignment to prevent epilepsy. We found that LGI1-ADAM22 instructs PSD-95 family membrane-associated guanylate kinases (MAGUKs) to organize transsynaptic protein networks, including NMDA/AMPA receptors, Kv1 channels, and LRRTM4-Neurexin adhesion molecules. Adam22ΔC5/ΔC5 knock-in mice devoid of the ADAM22-MAGUK interaction display lethal epilepsy of hippocampal origin, representing the mouse model for ADAM22-related epileptic encephalopathy. This model shows less-condensed PSD-95 nanodomains, disordered transsynaptic nanoalignment, and decreased excitatory synaptic transmission in the hippocampus. Strikingly, without ADAM22 binding, PSD-95 cannot potentiate AMPA receptor-mediated synaptic transmission. Furthermore, forced coexpression of ADAM22 and PSD-95 reconstitutes nano-condensates in nonneuronal cells. Collectively, this study reveals LGI1-ADAM22-MAGUK as an essential component of transsynaptic nanoarchitecture for precise synaptic transmission and epilepsy prevention.

Keywords: AMPA receptor; LGI1–ADAM22; MAGUK; epilepsy; transsynaptic nanocolumn.

Publication types

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

MeSH terms

  • ADAM Proteins / genetics*
  • Animals
  • Brain / metabolism
  • Brain / pathology
  • Calcium-Binding Proteins / genetics
  • Disease Models, Animal
  • Epilepsy / genetics*
  • Epilepsy / pathology
  • Epilepsy / prevention & control
  • Gene Knock-In Techniques
  • Guanylate Kinases / genetics*
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Membrane Proteins / genetics
  • Mice
  • Nerve Tissue Proteins / genetics*
  • Neural Cell Adhesion Molecules / genetics
  • Receptors, AMPA / genetics
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Shaker Superfamily of Potassium Channels / genetics
  • Synaptic Transmission / genetics*


  • Calcium-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • LRRTM4 protein, mouse
  • Lgi1 protein, mouse
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Neural Cell Adhesion Molecules
  • Nrxn1 protein, mouse
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • Shaker Superfamily of Potassium Channels
  • Guanylate Kinases
  • ADAM Proteins
  • Adam22 protein, mouse