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Point mutant mice with hypersensitive alpha 4 nicotinic receptors show dopaminergic deficits and increased anxiety

Labarca, Cesar and Schwarz, Johannes and Deshpande, Purnima and Schwarz, Sigrid and Nowak, Mark W. and Fonck, Carlos and Nashmi, Raad and Kofuji, Paulo and Dang, Hong and Shi, Wenmei and Fidan, Melihat and Khakh, Baljit S. and Chen, Zhoufeng and Bowers, Barbara J. and Boulter, Jim and Wehner, Jeanne M. and Lester, Henry A. (2001) Point mutant mice with hypersensitive alpha 4 nicotinic receptors show dopaminergic deficits and increased anxiety. Proceedings of the National Academy of Sciences of the United States of America, 98 (5). pp. 2786-2791. ISSN 0027-8424. http://resolver.caltech.edu/CaltechAUTHORS:LABpnas01

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Abstract

Knock-in mice were generated that harbored a leucine-to-serine mutation in the alpha4 nicotinic receptor near the gate in the channel pore. Mice with intact expression of this hypersensitive receptor display dominant neonatal lethality. These mice have a severe deficit of dopaminergic neurons in the substantia nigra, possibly because the hypersensitive receptors are continuously activated by normal extracellular choline concentrations. A strain that retains the neo selection cassette in an intron has reduced expression of the hypersensitive receptor and is viable and fertile. The viable mice display increased anxiety, poor motor learning, excessive ambulation that is eliminated by very low levels of nicotine, and a reduction of nigrostriatal dopaminergic function upon aging. These knock-in mice provide useful insights into the pathophysiology of sustained nicotinic receptor activation and may provide a model for Parkinson's disease.


Item Type:Article
Additional Information:Copyright © 2001 by the National Academy of Sciences. Communicated by Norman Davidson, California Institute of Technology, Pasadena, CA, December 8, 2000 (received for review October 4, 2000). We thank Shirley Pease and her colleagues for generating and maintaining the mice. This research was supported by grants from the National Institutes of Health (NS-11756, MH-49176, DA-10156, and DA11836) and from the California Tobacco-Related Disease Research Program and by fellowships from the Alexander von Humboldt Foundation, the German Academic Exchange Foundation, and the Wellcome Trust. J.S. and P.D. contributed equally to this work. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Subject Keywords:RAT SUBSTANTIA-NIGRA, ACETYLCHOLINE-RECEPTORS, PARKINSONS-DISEASE, PROGENITOR CELLS, M2 DOMAIN, MODULATION, BEHAVIOR, LACKING, SUBUNIT, NEURONS
Record Number:CaltechAUTHORS:LABpnas01
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:LABpnas01
Alternative URL:http://dx.doi.org/10.1073/pnas.041582598
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:901
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:03 Nov 2005
Last Modified:26 Dec 2012 08:41

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