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The Journal of Neuroscience, April 1, 2003, 23(7):2582

Increased Sensitivity to Agonist-Induced Seizures, Straub Tail, and Hippocampal Theta Rhythm in Knock-In Mice Carrying Hypersensitive 4 Nicotinic Receptors

Carlos Fonck¹, Raad Nashmi¹, Purnima Deshpande¹, M. Imad Damaj², Michael J. Marks³, Anett Riedel⁴, Johannes Schwarz^{1, 4}, Allan C. Collins³, Cesar Labarca¹, and Henry A. Lester¹

¹ Division of Biology, California Institute of Technology, Pasadena, California 91125, ² Department of Pharmacology and Toxicology, Medical College of Virginia Campus/Virginia Commonwealth University, Richmond, Virginia 23298, ³ Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado 80309, and ⁴ Department of Neurology, University of Leipzig, Leipzig, Germany 04103

We studied a strain of exon replacement mice ("L9'S knock-in") whose 4 nicotinic receptor subunits have a leucine to serine mutation in the M2 region, 9' position (Labarca et al., 2001); this mutation renders 4-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_A receptor 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. ⁸⁶Rb 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 4 receptors in autosomal dominant nocturnal frontal-lobe epilepsy.

Key words: nicotinic receptor; ADNFLE; seizure; epilepsy; cholinergic; gain of function; knock-in; mouse

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Copyright © 2003 Society for Neuroscience  0270-6474/03/2372582-09$05.00/0

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