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Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3799-804. doi: 10.1073/pnas.0914537107. Epub 2010 Feb 2.

Disruption of LGI1-linked synaptic complex causes abnormal synaptic transmission and epilepsy.

Author information

1
Department of Cell Physiology, National Institutes of Natural Sciences, Okazaki 444-8787, Japan.

Abstract

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.

PMID:
20133599
PMCID:
PMC2840530
DOI:
10.1073/pnas.0914537107
[Indexed for MEDLINE]
Free PMC Article

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