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Nicotine-Induced Dystonic Arousal Complex in a Mouse Line Harboring a Human Autosomal-Dominant Nocturnal Frontal Lobe Epilepsy Mutation

Teper, Yaroslav and Whyte, Douglas and Cahir, Elizabeth and Lester, Henry A. and Grady, Sharon R. and Marks, Michael J. and Cohen, Bruce N. and Fonck, Carlos and McClure-Begley, Tristan and McIntosh, J. Michael and Labarca, Cesar and Lawrence, Andrew and Chen, Feng and Gantois, Ilse and Davies, Philip J. and Petrou, Steven and Murphy, Mark and Waddington, John and Horne, Malcolm K. and Berkovic, Samuel F. and Drago, John (2007) Nicotine-Induced Dystonic Arousal Complex in a Mouse Line Harboring a Human Autosomal-Dominant Nocturnal Frontal Lobe Epilepsy Mutation. Journal of Neuroscience, 27 (38). pp. 10128-10142. ISSN 0270-6474. PMCID PMC6672658. doi:10.1523/jneurosci.3042-07.2007.

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We generated a mouse line harboring an autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE) mutation: the α4 nicotinic receptor S248F knock-in strain. In this mouse, modest nicotine doses (1–2 mg/kg) elicit a novel behavior termed the dystonic arousal complex (DAC). The DAC includes stereotypical head movements, body jerking, and forelimb dystonia; these behaviors resemble some core features of ADNFLE. A marked Straub tail is an additional component of the DAC. Similar to attacks in ADNFLE, the DAC can be partially suppressed by the sodium channel blocker carbamazepine or by pre-exposure to a very low dose of nicotine (0.1 mg/kg). The DAC is centrally mediated, genetically highly penetrant, and, surprisingly, not associated with overt ictal electrical activity as assessed by (1) epidural or frontal lobe depth-electrode electroencephalography or (2) hippocampal c-fos-regulated gene expression. Heterozygous knock-in mice are partially protected from nicotine-induced seizures. The noncompetitive antagonist mecamylamine does not suppress the DAC, although it suppresses high-dose nicotine-induced wild-type-like seizures. Experiments on agonist-induced ⁸⁶Rb⁺ and neurotransmitter efflux from synaptosomes and on α4S248Fβ2 receptors expressed in oocytes confirm that the S248F mutation confers resistance to mecamylamine blockade. Genetic background, gender, and mutant gene expression levels modulate expression of the DAC phenotype in mice. The S248F mouse thus appears to provide a model for the paroxysmal dystonic element of ADNFLE semiology. Our model complements what is seen in other ADNFLE animal models. Together, these mice cover the spectrum of behavioral and electrographic events seen in the human condition.

Item Type:Article
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URLURL TypeDescription CentralArticle
Lester, Henry A.0000-0002-5470-5255
Cohen, Bruce N.0000-0003-2913-6238
Additional Information:© 2007 Society for Neuroscience. Received Nov. 21, 2006; revised Aug. 1, 2007; accepted Aug. 1, 2007. This work was supported by National Health and Medical Research Council (NHMRC) Program Grant 236805 and National Institutes of Health Grant MH53631 to J.M.M.; National Institute on Drug Abuse Grants DA003194, DA012242, and DA015663; National Institute of Neurological Disorders and Stroke Grants NS43800 and NS046464; and Science Foundation Ireland Grant 02-1N1B227. J.D. is an NHMRC Practitioner fellow. We thank Vincenzo Ferreri, Jim Massalas, Keith Buxton, and Yvette Wilson for technical assistance and Dr. Rachael Nally and Associate Prof. Ian Gordon for advice with statistical analysis. We are grateful to Dr. Jim Boulter for providing genomic DNA clones used to build the original L9S' targeting construct. We are grateful to Prof. Ingrid Scheffer for critical input and discussion on clinical aspects of ADNFLE.
Funding AgencyGrant Number
National Health and Medical Research Council (NHMRC)236805
Science Foundation, Ireland02-1N1B227
Subject Keywords:nicotine; epilepsy; ADNFLE; dystonia; mecamylamine; synaptosome
Issue or Number:38
PubMed Central ID:PMC6672658
Record Number:CaltechAUTHORS:20200422-080631596
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Official Citation:Nicotine-Induced Dystonic Arousal Complex in a Mouse Line Harboring a Human Autosomal-Dominant Nocturnal Frontal Lobe Epilepsy Mutation. Yaroslav Teper, Douglas Whyte, Elizabeth Cahir, Henry A. Lester, Sharon R. Grady, Michael J. Marks, Bruce N. Cohen, Carlos Fonck, Tristan McClure-Begley, J. Michael McIntosh, Cesar Labarca, Andrew Lawrence, Feng Chen, Ilse Gantois, Philip J. Davies, Steven Petrou, Mark Murphy, John Waddington, Malcolm K. Horne, Samuel F. Berkovic, John Drago. Journal of Neuroscience 19 September 2007, 27 (38) 10128-10142; DOI: 10.1523/JNEUROSCI.3042-07.2007
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:102711
Deposited By: Tony Diaz
Deposited On:22 Apr 2020 15:18
Last Modified:04 Mar 2022 16:39

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