LGI1-associated epilepsy through altered ADAM23-dependent neuronal morphology

Mol Cell Neurosci. 2009 Dec;42(4):448-57. doi: 10.1016/j.mcn.2009.09.008. Epub 2009 Sep 29.


Most epilepsy genes encode ion channels, but the LGI1 gene responsible for autosomal dominant partial epilepsy with auditory features produces a secreted protein. LGI1 is suggested to regulate PSD-95 via ADAM22. However, no unbiased screen of LGI1 action has been conducted. Here, we searched for brain genes supporting high affinity LGI-1 binding. ADAM23 was the only LGI1 interactor identified. The related proteins, ADAM22 and ADAM11, but not ADAM12, bind LGI1. Neither ADAM23 nor ADAM11, nor some forms of ADAM22, contain PDZ-interacting sequences, suggesting PSD-95-independent mechanisms in ADPEAF. Because ADAMs modulate integrins, we examined LGI1 effect on neurite outgrowth. LGI1 increases outgrowth from wild-type but not ADAM23-/- neurons. Furthermore, CA1 pyramidal neurons of ADAM23-/- hippocampi have reduced dendritic arborization. ADAM23-/- mice exhibit spontaneous seizures, while ADAM23+/- mice have decreased seizure thresholds. Thus, LGI1 binding to ADAM23 is necessary to correctly pattern neuronal morphology and altered anatomical patterning contributes to ADPEAF.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ADAM Proteins / genetics
  • ADAM Proteins / metabolism*
  • Animals
  • Behavior, Animal / physiology
  • Binding Sites
  • Brain / anatomy & histology
  • Brain / metabolism
  • COS Cells
  • Chlorocebus aethiops
  • Epilepsy / genetics
  • Epilepsy / metabolism*
  • Epilepsy / physiopathology
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurons / cytology*
  • Neurons / metabolism
  • Phenotype
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Proteins / genetics
  • Proteins / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism


  • Intracellular Signaling Peptides and Proteins
  • LGI1 protein, human
  • Nerve Tissue Proteins
  • Protein Isoforms
  • Proteins
  • Recombinant Fusion Proteins
  • ADAM Proteins
  • Adam23 protein, mouse