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Enhanced expression of hypersensitive α4* nAChR in adult mice increases the loss of midbrain dopaminergic neurons

Schwarz, Johannes and Schwarz, Sigrid C. and Dorigo, Oliver and Stützer, Alexandra and Wegner, Florian and Labarca, Cesar and Deshpande, Purnima and Gil, Jose S. and Berk, Arnold J. and Lester, Henry A. (2006) Enhanced expression of hypersensitive α4* nAChR in adult mice increases the loss of midbrain dopaminergic neurons. FASEB Journal, 20 (7). pp. 935-946. ISSN 0892-6638. doi:10.1096/fj.05-5497com.

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We describe an inducible genetic model for degeneration of midbrain dopaminergic neurons in adults. In previous studies, knock-in mice expressing hypersensitive M2 domain Leu9’Ser (L9’S) α4 nicotinic receptors (nAChR) at near-normal levels displayed dominant neonatal lethality and dopaminergic deficits in embryonic midbrain, because the hypersensitive nAChR is excitotoxic. However, heterozygous L9’S mice that retain the neomycin resistance cassette (neo) in a neighboring intron express low levels of the mutant allele (∼25% of normal levels), and these neo-intact mice are therefore viable and fertile. The neo cassette is flanked by loxP sites. In adult animals, we locally injected helper-dependent adenovirus (HDA) expressing cre recombinase. Local excision of the neo cassette, via cre-mediated recombination, was verified by genomic analysis. In L9’S HDA-cre injected animals, locomotion was reduced both under baseline conditions and after amphetamine application. There was no effect in L9’S HDA-control treated animals or in wild-type (WT) littermates injected with either virus. Immunocytochemical analyses revealed marked losses (> 70%) of dopaminergic neurons in L9’S HDA-cre injected mice compared to controls. At 20–33 days postinjection in control animals, the coexpressed marker gene, yellow fluorescent protein (YFP), was expressed in many neurons and few glial cells near the injection, emphasizing the neurotropic utility of the HDA. Thus, HDA-mediated gene transfer into adult midbrain induced sufficient functional expression of cre in dopaminergic neurons to allow for postnatal deletion of neo. This produced increased L9’S mutant nAChR expression, which in turn led to nicotinic cholinergic excitotoxicity in dopaminergic neurons.

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Lester, Henry A.0000-0002-5470-5255
Additional Information:© 2006 Federation of American Societies for Experimental Biology. Received for publication November 28, 2005. Accepted for publication December 19, 2005. Acknowledgments: Deutsche Forschungsgemeinschaft 704/3–1, IZKF-Leipzig TP C27, California; Tobacco-Related Disease Research Program, National Parkinson Foundation, Keck Foundation, Plum Foundation, NIH (NS-11756, MH-49176); and a UCLA Human Gene Therapy seed grant. O.D. was supported by a grant from the American Association of Obstetricians and Gynecologists Foundation (AAOGF). J.S.G. received partial support from U.S. Public Health Service National Research Service award GM07185 and a Cota Robles Fellowship. We thank Ralf Schober for assistance with ICC images.
Funding AgencyGrant Number
Deutsche Forschungsgemeinschaft (DFG)704/3–1
ZKF-LeipzigTP C27
California Tobacco-Related Disease Research ProgramUNSPECIFIED
National Parkinson FoundationUNSPECIFIED
W. M. Keck FoundationUNSPECIFIED
Plum FoundationUNSPECIFIED
UCLA Human Gene Therapy seed grantUNSPECIFIED
American Association of Obstetricians and Gynecologists FoundationUNSPECIFIED
NIH Predoctoral FellowshipGM07185
Cota Robles FellowshipUNSPECIFIED
Subject Keywords:nicotinic receptor; substantia nigra; cholinergic excitotoxicity; knock-in mouse; helper-dependent adenovirus; Parkinson’s disease
Issue or Number:7
Record Number:CaltechAUTHORS:20170408-135451181
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Official Citation:Johannes Schwarz, Sigrid C. Schwarz, Oliver Dorigo, Alexandra Stützer, Florian Wegner, Cesar Labarca, Purnima Deshpande, Jose S. Gil, Arnold J. Berk, and Henry A. Lester Enhanced expression of hypersensitive α4* nAChR in adult mice increases the loss of midbrain dopaminergic neurons FASEB J May 2006 20:935-946; doi:10.1096/fj.05-5497com
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:75885
Deposited By: 1Science Import
Deposited On:13 Apr 2017 21:01
Last Modified:03 Oct 2019 16:55

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