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. doi:10.1523/jneurosci.23-07-02582.2003. 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.
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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. | ||||||||||||||||
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Subject Keywords: | nicotinic receptor; ADNFLE; seizure; epilepsy; cholinergic; gain of function; knock-in; mouse | ||||||||||||||||
Issue or Number: | 7 | ||||||||||||||||
PubMed Central ID: | PMC6742094 | ||||||||||||||||
DOI: | 10.1523/jneurosci.23-07-02582.2003 | ||||||||||||||||
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: | 02 Mar 2022 00:49 |
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