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The Journal of Neuroscience, December 7, 2005, 25(49):11396-11411; doi:10.1523/JNEUROSCI.3597-05.2005

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Neurobiology of Disease
Novel Seizure Phenotype and Sleep Disruptions in Knock-In Mice with Hypersensitive 4^* Nicotinic Receptors

Carlos Fonck,¹ Bruce N. Cohen,¹ Raad Nashmi,¹ Paul Whiteaker,³ Daniel A. Wagenaar,² Nivalda Rodrigues-Pinguet,¹ Purnima Deshpande,¹ Sheri McKinney,¹ Steven Kwoh,¹ Jose Munoz,¹ Cesar Labarca,¹ Allan C. Collins,³ Michael J. Marks,³ and Henry A. Lester¹

Divisions of ¹Biology and ²Physics, Mathematics, and Astronomy, California Institute of Technology, Pasadena, California 91125, and ³Institute for Behavioral Genetics, University of Colorado at Boulder, Boulder, Colorado 80309

A leucine to alanine substitution (L9'A) was introduced in the M2 region of the mouse 4 neuronal nicotinic acetylcholine receptor (nAChR) subunit. Expressed in Xenopus oocytes, 4(L9'A)2 nAChRs were 30-fold more sensitive than wild type (WT) to both ACh and nicotine. We generated knock-in mice with the L9'A mutation and studied their cellular responses, seizure phenotype, and sleep-wake cycle. Seizure studies on 4-mutated animals are relevant to epilepsy research because all known mutations linked to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) occur in the M2 region of 4or 2 subunits. Thalamic cultures and synaptosomes from L9'A mice were hypersensitive to nicotine-induced ion flux. L9'A mice were 15-fold more sensitive to seizures elicited by nicotine injection than their WT littermates. Seizures in L9'A mice differed qualitatively from those in WT: L9'A seizures started earlier, were prevented by nicotine pretreatment, lacked EEG spike-wave discharges, and consisted of fast repetitive movements. Nicotine-induced seizures in L9'A mice were partial, whereas WT seizures were generalized. When L9'A homozygous mice received a 10 mg/kg nicotine injection, there was temporal and phenomenological separation of mutant and WT-like seizures: an initial seizure 20 s after injection was clonic and showed no EEG changes. A second seizure began 3-4 min after injection, was tonic-clonic, and had EEG spike-wave activity. No spontaneous seizures were detected in L9'A mice during chronic video/EEG recordings, but their sleep-wake cycle was altered. Our findings show that hypersensitive 4^* nicotinic receptors in mice mediate changes in the sleep-wake cycle and nicotine-induced seizures resembling ADNFLE.

Key words: epilepsy; ADNFLE; nicotinic receptors; sleep disorders; 42; nicotine

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Received Feb 9, 2005; revised October 18, 2005; accepted October 21, 2005.

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