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Mice expressing the ADNFLE valine 287 leucine mutation of the Β2 nicotinic acetylcholine receptor subunit display increased sensitivity to acute nicotine administration and altered presynaptic nicotinic receptor function

O'Neill, Heidi C. and Laverty, Duncan C. and Patzlaff, Natalie E. and Cohen, Bruce N. and Fonck, Carlos and McKinney, Sheri and McIntosh, J. Michael and Lindstrom, Jon M. and Lester, Henry A. and Grady, Sharon R. and Marks, Michael J. (2013) Mice expressing the ADNFLE valine 287 leucine mutation of the Β2 nicotinic acetylcholine receptor subunit display increased sensitivity to acute nicotine administration and altered presynaptic nicotinic receptor function. Pharmacology Biochemistry and Behavior, 103 (3). pp. 603-621. ISSN 0091-3057. PMCID PMC3544981. doi:10.1016/j.pbb.2012.10.014. https://resolver.caltech.edu/CaltechAUTHORS:20130319-103616459

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Abstract

Several mutations in α4 or β2 nicotinic receptor subunits are linked to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). One such missense mutation in the gene encoding the β2 neuronal nicotinic acetylcholine receptor (nAChR) subunit (CHRNB2) is a valine-to-leucine substitution in the second transmembrane domain at position 287 (β2VL). Previous studies indicated that the β2VL mutation in mice alters circadian rhythm consistent with sleep alterations observed in ADNFLE patients (Xu et al., 2011). The current study investigates changes in nicotinic receptor function and expression that may explain the behavioral phenotype of β2VL mice. No differences in β2 mRNA expression were found between wild-type (WT) and heterozygous (HT) or homozygous mutant (MT) mice. However, antibody and ligand binding indicated that the mutation resulted in a reduction in receptor protein. Functional consequences of the β2VL mutation were assessed biochemically using crude synaptosomes. A gene-dose dependent increase in sensitivity to activation by acetylcholine and decrease in maximal nAChR-mediated [^3H]-dopamine release and ^(86)Rb efflux were observed. Maximal nAChR-mediated [^3H]-GABA release in the cortex was also decreased in the MT, but maximal [^3H]-GABA release was retained in the hippocampus. Behaviorally both HT and MT mice demonstrated increased sensitivity to nicotine-induced hypolocomotion and hypothermia. Furthermore, WT mice display only a tonic–clonic seizure (EEG recordable) 3 min after injection of a high dose of nicotine, while MT mice also display a dystonic arousal complex (non-EEG recordable) event 30 s after nicotine injection. Data indicate decreases in maximal response for certain measures are larger than expected given the decrease in receptor expression.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1016/j.pbb.2012.10.014DOIArticle
http://www.sciencedirect.com/science/article/pii/S0091305712003061PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3544981PubMed CentralArticle
ORCID:
AuthorORCID
Lester, Henry A.0000-0002-5470-5255
Additional Information:© 2012 Elsevier Inc. Received 25 July 2012. Received in revised form 26 September 2012. Accepted 24 October 2012. Available online 1 November 2012. The authors thank Jian Xuand Steve Heinemannatthe SalkInstitute, La Jolla, CA for initially supplying the β2VL mutant mice. This work was supported by grants R01 DA003194, R01 DA012242, P30 DA015663 and U19 DA019375 to MJM; R01 GM 103801 and R01 GM 48677 to JMM; R01 NS 11323 to JML
Funders:
Funding AgencyGrant Number
NIHR01 DA003194
NIHR01 DA012242
NIHP30 DA015663
NIHU19 DA019375
NIHR01 GM 103801
NIHR01 GM 48677
NIHR01 NS 11323
Subject Keywords:Nicotinic acetylcholine receptor; Autosomal dominant nocturnal frontal lobe epilepsy; Nicotine; Autoradiography; Knock-in mouse; Synaptosomes
Issue or Number:3
PubMed Central ID:PMC3544981
DOI:10.1016/j.pbb.2012.10.014
Record Number:CaltechAUTHORS:20130319-103616459
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20130319-103616459
Official Citation:Heidi C. O'Neill, Duncan C. Laverty, Natalie E. Patzlaff, Bruce N. Cohen, Carlos Fonck, Sheri McKinney, J. Michael McIntosh, Jon M. Lindstrom, Henry A. Lester, Sharon R. Grady, Michael J. Marks, Mice expressing the ADNFLE valine 287 leucine mutation of the Β2 nicotinic acetylcholine receptor subunit display increased sensitivity to acute nicotine administration and altered presynaptic nicotinic receptor function, Pharmacology Biochemistry and Behavior, Volume 103, Issue 3, January 2013, Pages 603-621, ISSN 0091-3057, 10.1016/j.pbb.2012.10.014. (http://www.sciencedirect.com/science/article/pii/S0091305712003061)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:37559
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:19 Mar 2013 18:10
Last Modified:09 Nov 2021 23:29

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