Disruption of LGI1-linked synaptic complex causes abnormal synaptic transmission and epilepsy.
Epilepsy is a devastating and poorly understood disease. Mutations in a secreted neuronal protein, leucine-rich glioma inactivated 1 (LGI1), were reported in patients with an inherited form of human epilepsy, autosomal dominant partial epilepsy with auditory features (ADPEAF). Here, we report an essential role of LGI1 as an antiepileptogenic ligand. We find that loss of LGI1 in mice (LGI1(-/-)) causes lethal epilepsy, which is specifically rescued by the neuronal expression of LGI1 transgene, but not LGI3. Moreover, heterozygous mice for the LGI1 mutation (LGI1(+/-)) show lowered seizure thresholds. Extracellularly secreted LGI1 links two epilepsy-related receptors, ADAM22 and ADAM23, in the brain and organizes a transsynaptic protein complex that includes presynaptic potassium channels and postsynaptic AMPA receptor scaffolds. A lack of LGI1 disrupts this synaptic protein connection and selectively reduces AMPA receptor-mediated synaptic transmission in the hippocampus. Thus, LGI1 may serve as a major determinant of brain excitation, and the LGI1 gene-targeted mouse provides a good model for human epilepsy.
Department of Cell Physiology, National Institutes of Natural Sciences, Okazaki 444-8787, Japan.
Yuko
Y
Fukata
Kathryn L
KL
Lovero
Tsuyoshi
T
Iwanaga
Atsushi
A
Watanabe
Norihiko
N
Yokoi
Katsuhiko
K
Tabuchi
Ryuichi
R
Shigemoto
Roger A
RA
Nicoll
Masaki
M
Fukata
D051722:ADAM Proteins / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D020937:Epilepsy, Partial, Sensory / Q000235:genetics* / Q000503:physiopathology; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D009435:Synaptic Transmission / Q000235:genetics*
D047908:Intracellular Signaling Peptides and Proteins; C492120:Lgi1 protein, mouse; D009419:Nerve Tissue Proteins; D011506:Proteins; D018091:Receptors, AMPA; D051722:ADAM Proteins; C121258:Adam22 protein, mouse; C121259:Adam23 protein, mouse