Journal article
Seizures and enhanced cortical GABAergic inhibition in two mouse models of human autosomal dominant nocturnal frontal lobe epilepsy
Proceedings of the National Academy of Sciences - PNAS, Vol.103(50), pp.19152-19157
12/12/2006
DOI: 10.1073/pnas.0608215103
PMCID: PMC1681351
PMID: 17146052
Abstract
Selected mutations in the human α4 or β2 neuronal nicotinic acetylcholine receptor subunit genes cosegregate with a partial epilepsy syndrome known as autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). To examine possible mechanisms underlying this inherited epilepsy, we engineered two ADNFLE mutations (Chrna4S252F and Chrna4+L264) in mice. Heterozygous ADNFLE mutant mice show persistent, abnormal cortical electroencephalograms with prominent delta and theta frequencies, exhibit frequent spontaneous seizures, and show an increased sensitivity to the proconvulsant action of nicotine. Relative to WT, electrophysiological recordings from ADNFLE mouse layer II/III cortical pyramidal cells reveal a >20-fold increase in nicotine-evoked inhibitory postsynaptic currents with no effect on excitatory postsynaptic currents. i.p. injection of a subthreshold dose of picrotoxin, a use-dependent γ-aminobutyric acid receptor antagonist, reduces cortical electroencephalogram delta power and transiently inhibits spontaneous seizure activity in ADNFLE mutant mice. Our studies suggest that the mechanism underlying ADNFLE seizures may involve inhibitory synchronization of cortical networks via activation of mutant α4-containing nicotinic acetylcholine receptors located on the presynaptic terminals and somatodendritic compartments of cortical GABAergic interneurons.
Details
- Title: Subtitle
- Seizures and enhanced cortical GABAergic inhibition in two mouse models of human autosomal dominant nocturnal frontal lobe epilepsy
- Creators
- Alwin Klaassen - Graduate Interdepartmental Program in Neuroscience, 675 Charles Young Drive South, University of California, Los Angeles, CA 90095Joseph Glykys - Graduate Interdepartmental Program in Neuroscience, 675 Charles Young Drive South, University of California, Los Angeles, CA 90095Jamie Maguire - Department of Neurology, 655 Charles Young Drive South, University of California, Los Angeles, CA 90095; andCesar Labarca - Division of Biology, California Institute of Technology, Pasadena, CA 91125Istvan Mody - Department of Neurology, 655 Charles Young Drive South, University of California, Los Angeles, CA 90095; andJim Boulter - Department of Psychiatry and Biobehavioral Sciences, Hatos Research Center for Neuropharmacology, Brain Research and Molecular Biology Institutes, and
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.103(50), pp.19152-19157
- DOI
- 10.1073/pnas.0608215103
- PMID
- 17146052
- PMCID
- PMC1681351
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Language
- English
- Date published
- 12/12/2006
- Academic Unit
- Neurology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neurology (Pediatrics)
- Record Identifier
- 9984020788902771
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