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Increased Sensitivity to Agonist-Induced Seizures, Straub Tail, and Hippocampal Theta Rhythm in Knock-In Mice Carrying Hypersensitive α4 Nicotinic Receptors

Fonck, Carlos and Nashmi, Raad and Deshpande, Purnima and Damaj, M. Imad and Marks, Michael J. and Riedel, Anett and Schwarz, Johannes and Collins, Allan C. and Labarca, Cesar and Lester, Henry A. (2003) Increased Sensitivity to Agonist-Induced Seizures, Straub Tail, and Hippocampal Theta Rhythm in Knock-In Mice Carrying Hypersensitive α4 Nicotinic Receptors. Journal of Neuroscience, 23 (7). pp. 2582-2590. ISSN 0270-6474. PMCID PMC6742094. https://resolver.caltech.edu/CaltechAUTHORS:20190927-090347351

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Abstract

We studied a strain of exon replacement mice (“L9′S knock-in”) whose α4 nicotinic receptor subunits have a leucine to serine mutation in the M2 region, 9′ position (Labarca et al., 2001); this mutation renders α4-containing receptors hypersensitive to agonists. Nicotine induced seizures at concentrations (1 mg/kg) approximately eight times lower in L9′S than in wild-type (WT) littermates. At these concentrations, L9′S but not WT showed increases in EEG amplitude and theta rhythm. L9′S mice also showed higher seizure sensitivity to the nicotinic agonist epibatidine, but not to the GABA_Areceptor blocker and proconvulsant bicuculline. Dorsiflexion of the tail (Straub tail) was the most sensitive nicotine effect found in L9′S mice (0.1 mg/kg). The L9′S mice were hypersensitive to galanthamine- and tacrine-induced seizures and Straub tails. There were no apparent neuroanatomical differences between L9′S and WT mice in several brain regions. [125I]Epibatidine binding to brain membranes showed that the mutant allele was expressed at ∼25% of WT levels, presumably because of the presence of a neomycin selection cassette in a nearby intron. ^(86)Rb efflux experiments on brain synaptosomes showed an increased fraction of function at low agonist concentrations in L9′S mice. These data support the possible involvement of gain-of-function α4 receptors in autosomal dominant nocturnal frontal-lobe epilepsy.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1523/jneurosci.23-07-02582.2003DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742094PubMed CentralArticle
ORCID:
AuthorORCID
Lester, Henry A.0000-0002-5470-5255
Additional Information:© 2003 Society for Neuroscience. Received Sept. 17, 2002; revised Dec. 24, 2002; accepted Jan. 13, 2003. This work was supported by the Tobacco-Related Disease Research Program; by the Keck Foundation; by National Institutes of Health Grants NS-117656, MH-49176, DA-10156, and DA-11836; and by a National Research Service Award to C.F. We thank Jim Boulter, Bruce Cohen, Bonnie Davis, Ken Davis, Sharon Grady, Margaret Jacobs, Yuan Liu, and Jeanne Wehner for discussion; Sarah McCallum for experiments on GABA release; Istvan Mody and Enric Claverol for teaching us electroencephalography; and Bronagh Glaser for administrative assistance.
Funders:
Funding AgencyGrant Number
California Tobacco-Related Disease Research ProgramUNSPECIFIED
W. M. Keck FoundationUNSPECIFIED
NIHNS-117656
NIHMH-49176
NIHDA-10156
NIHDA-11836
NIH Predoctoral FellowshipUNSPECIFIED
Subject Keywords:nicotinic receptor; ADNFLE; seizure; epilepsy; cholinergic; gain of function; knock-in; mouse
Issue or Number:7
PubMed Central ID:PMC6742094
Record Number:CaltechAUTHORS:20190927-090347351
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20190927-090347351
Official Citation:Increased Sensitivity to Agonist-Induced Seizures, Straub Tail, and Hippocampal Theta Rhythm in Knock-In Mice Carrying Hypersensitive α4 Nicotinic Receptors. Carlos Fonck, Raad Nashmi, Purnima Deshpande, M. Imad Damaj, Michael J. Marks, Anett Riedel, Johannes Schwarz, Allan C. Collins, Cesar Labarca, Henry A. Lester. Journal of Neuroscience 1 April 2003, 23 (7) 2582-2590; DOI: 10.1523/JNEUROSCI.23-07-02582.2003
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:98898
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:27 Sep 2019 18:09
Last Modified:03 Oct 2019 21:45

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