A Caltech Library Service

Novel Seizure Phenotype and Sleep Disruptions in Knock-In Mice with Hypersensitive α4* Nicotinic Receptors

Fonck, Carlos and Cohen, Bruce N. and Nashmi, Raad and Whiteaker, Paul and Wagenaar, Daniel A. and Rodrigues-Pinguet, Nivalda and Deshpande, Purnima and McKinney, Sheri and Kwoh, Steven and Munoz, Jose and Labarca, Cesar and Collins, Allan C. and Marks, Michael J. and Lester, Henry A. (2005) Novel Seizure Phenotype and Sleep Disruptions in Knock-In Mice with Hypersensitive α4* Nicotinic Receptors. Journal of Neuroscience, 25 (49). pp. 11396-11411. ISSN 0270-6474. PMCID PMC6725918. doi:10.1523/jneurosci.3597-05.2005.

[img] PDF - Published Version
See Usage Policy.


Use this Persistent URL to link to this item:


A leucine to alanine substitution (L9′A) was introduced in the M2 region of the mouse α4 neuronal nicotinic acetylcholine receptor (nAChR) subunit. Expressed in Xenopus oocytes, α4(L9′A)β2 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 α4-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 α4or β2 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 α4* nicotinic receptors in mice mediate changes in the sleep-wake cycle and nicotine-induced seizures resembling ADNFLE.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle
Wagenaar, Daniel A.0000-0002-6222-761X
Lester, Henry A.0000-0002-5470-5255
Additional Information:© 2005 Society for Neuroscience. Received Feb. 9, 2005; revised Oct. 18, 2005; accepted Oct. 21, 2005. This work was supported by National Institute of Health Grants NS46464, NS43800, NS11756, DA10156, DA03194, and DA17279 and a National Institutes of Health–National Research Service Award (C.F.). The California Tobacco-Related Disease Research Program and Philip Morris USA/International are gratefully acknowledged. We thank J. Stitzel for the mouse α4 cDNA, Chana Simon for oocyte data analysis, Robert Paz for help with photography, and Sharon Grady, Andrew Tapper, and Johannes Schwarz for insightful discussion.
Funding AgencyGrant Number
NIH Predoctoral FellowshipUNSPECIFIED
California Tobacco-Related Disease Research ProgramUNSPECIFIED
Philip Morris USA/InternationalUNSPECIFIED
Subject Keywords:epilepsy; ADNFLE; nicotinic receptors; sleep disorders; α4β2; nicotine
Issue or Number:49
PubMed Central ID:PMC6725918
Record Number:CaltechAUTHORS:20200427-144703784
Persistent URL:
Official Citation:Novel Seizure Phenotype and Sleep Disruptions in Knock-In Mice with Hypersensitive α4* Nicotinic Receptors. Carlos Fonck, Bruce N. Cohen, Raad Nashmi, Paul Whiteaker, Daniel A. Wagenaar, Nivalda Rodrigues-Pinguet, Purnima Deshpande, Sheri McKinney, Steven Kwoh, Jose Munoz, Cesar Labarca, Allan C. Collins, Michael J. Marks, Henry A. Lester. Journal of Neuroscience 7 December 2005, 25 (49) 11396-11411; DOI: 10.1523/JNEUROSCI.3597-05.2005
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:102816
Deposited By: Tony Diaz
Deposited On:27 Apr 2020 22:26
Last Modified:16 Nov 2021 18:15

Repository Staff Only: item control page