Altered neuronal circuits as the basis for ADPEAF epilepsy: LGI1 binding to ADAM23 is required for dendritic morphology

Human epilepsy assumes diverse clinical courses and has many causes, including genetic predisposition. While nearly all human epilepsy-related genes encode ion channels, the mutant gene responsible for Autosomal Dominant Partial Epilepsy with Auditory Features (ADPEAF) does not. The gene causing 50% of ADPEAF cases encodes the LGI1 protein. Various mechanisms for LGI1 mutant-dependent epilepsy have been suggested. Schulte et al. (2006) reported that intracellular LGI1 modulated the inactivation rate of a voltage-gated K channel. However, numerous groups have shown that the majority of LGI1 protein is secreted. In an alternate pathway, Fukata et al. (2006) found that secreted LGI1 can bind to a rare isoform of transmembrane ADAM22 to alter PSD-95 and hence AMPA-receptor mediated synaptic transmission. However, the majority of ADAM22 isoforms and all of the related LGI1-binding ADAMs do not contain the PDZ-binding motifs capable of interacting with PSD-95. No unbiased genome based screen for LGI1 interactors has been conducted and no ion channel independent mechanism for LGI1 action in ADPEAF has been suggested.We screened a mouse cDNA library with LGI1 as a ligand and isolated ADAM23 as a high affinity interactor. We find that LGI1 also binds the closely related ADAM22 and ADAM11, but not ADAM12. We also show that LGI1 increases outgrowth of hippocampal and cortical neurons in-vitro, and that neurons from mice lacking ADAM23 show reduced outgrowth stimulation by LG11. We show that ADAM23 -/- mice exhibit clinical seizures in the neonatal period and adult ADAM23 +/- mice have decreased threshold to chemically induced seizures. Furthermore, pyramidal neurons in the CA1 region of ADAM23 -/- mice hippocampi have significantly reduced area of dendritic arborization. We conclude that LGI1 binding to ADAM22/23/11 is necessary to correctly pattern neuronal morphology and prevent an anatomically engendered epilepsy in ADPEAF.