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The Journal of Neuroscience, September 19, 2007, 27(38):10128-10142; doi:10.1523/JNEUROSCI.3042-07.2007

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

Yaroslav Teper,¹ Douglas Whyte,¹ Elizabeth Cahir,¹ Henry A. Lester,³ Sharon R. Grady,⁴ Michael J. Marks,⁴ Bruce N. Cohen,³ Carlos Fonck,³ Tristan McClure-Begley,⁴ J. Michael McIntosh,⁵ Cesar Labarca,³ Andrew Lawrence,¹ Feng Chen,¹ Ilse Gantois,¹ Philip J. Davies,¹ Steven Petrou,¹ Mark Murphy,² John Waddington,⁶ Malcolm K. Horne,¹ Samuel F. Berkovic,⁷ and John Drago¹

¹Howard Florey Institute and ²Department of Anatomy and Cell Biology, The University of Melbourne, Victoria 3010, Australia, ³Division of Biology, California Institute of Technology, Pasadena, California 91125, ⁴Institute of Behavioral Genetics, University of Colorado, Boulder, Colorado 80309, ⁵Departments of Biology and Psychiatry, University of Utah, Salt Lake City, Utah 84112-0840, ⁶Royal College of Surgeons in Ireland, Dublin 2, Ireland, and ⁷Department of Medicine and Epilepsy Research Centre, University of Melbourne, Austin Health, Heidelberg West, Victoria 3081, Australia

Correspondence should be addressed to John Drago, Associate Professor, Howard Florey Institute, The University of Melbourne, Victoria 3010, Australia. Email: j.drago{at}hfi.unimelb.edu.au

We generated a mouse line harboring an autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE) mutation: the 4 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 4S248Fß2 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.

Key words: nicotine; epilepsy; ADNFLE; dystonia; mecamylamine; synaptosome

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Received Nov. 21, 2006; revised Aug. 1, 2007; accepted Aug. 1, 2007.

Correspondence should be addressed to John Drago, Associate Professor, Howard Florey Institute, The University of Melbourne, Victoria 3010, Australia. Email: j.drago{at}hfi.unimelb.edu.au

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