Point mutant mice with hypersensitive α4 nicotinic receptors show dopaminergic deficits and increased anxiety

Cesar Labarca, Johannes Schwarz, Purnima Deshpande, Sigrid Schwarz, Mark W. Nowak, Carlos Fonck, Raad Nashmi, Paulo Kofuji, Hong Dang, Wenmei Shi, Melihat Fidan, Baljit S. Khakh, Zhoufeng Chen, Barbara J. Bowers, Jim Boulter, Jeanne M. Wehner, Henry A. Lester

Research output: Contribution to journalArticlepeer-review

149 Scopus citations

Abstract

Knock-in mice were generated that harbored a leucine-to-serine mutation in the α4 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.

Original languageEnglish (US)
Pages (from-to)2786-2791
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number5
DOIs
StatePublished - Feb 27 2001

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