Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 8, Pages 3799-3804Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0914537107
Keywords
ADPEAF; AMPA-type glutamate receptor; ADAM22; ADAM23; ligand/receptor
Categories
Funding
- Human Frontier Science Program HFSP [CDA0015-07]
- Ministry of Education, Culture, Sports, Science and Technology of Japan MEXT [21680029, 20670005, 20022043, 20054022]
- National Institute of Mental Health
- HFSP [RGY0059-06]
- Grants-in-Aid for Scientific Research [21680029, 20054022, 20670005, 20022043] Funding Source: KAKEN
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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.
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