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Knockin mice with Leu9′Ser α4-nicotinic receptors: substantia nigra dopaminergic neurons are hypersensitive to agonist and lost postnatally

Orb, Sabine and Wieacker, Johannes and Labarca, Cesar and Fonck, Carlos and Lester, Henry A. and Schwarz, Johannes (2004) Knockin mice with Leu9′Ser α4-nicotinic receptors: substantia nigra dopaminergic neurons are hypersensitive to agonist and lost postnatally. Physiological Genomics, 18 (3). pp. 299-307. ISSN 1094-8341. https://resolver.caltech.edu/CaltechAUTHORS:20200422-150959788

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Abstract

This study analyzes the electrophysiological cause and behavioral consequence of dopaminergic cell loss in a knockin mouse strain bearing hypersensitive nicotinic α4-receptor subunits (“L9′S mice”). Adult brains of L9′S mice show moderate loss of substantia nigra dopaminergic neurons and of striatal dopaminergic innervation. Amphetamine-stimulated locomotion is impaired, reflecting a reduction of dopamine stored in presynaptic vesicles. Recordings from dopaminergic neurons in L9′S mice show that 10 μM nicotine depolarizes cells and increases spiking rates in L9′S cells but hyperpolarizes and decreases spiking rates in wild-type (WT) cells. Thus dopaminergic neurons of L9′S mice have an excitatory response to nicotine which is qualitatively different from that of WT neurons. The cause of dopaminergic cell death is therefore probably an increased sensitivity to acetylcholine or choline of α4-containing nicotinic receptors. Hypersensitive excitatory stimulation during activation of α4-containing receptors provides the first evidence for cholinergic excitotoxicity as a cause of dopaminergic neuron death. This novel concept may be relevant to the pathophysiology of Parkinson disease.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1152/physiolgenomics.00012.2004DOIArticle
ORCID:
AuthorORCID
Lester, Henry A.0000-0002-5470-5255
Additional Information:© 2004 the American Physiological Society. Submitted 16 January 2004; accepted in final form 7 June 2004. This work was supported by German Research Foundation Grant DFG 704/3-1, the Tobacco Related Disease Research Project of California, NS-11756 and MH-49176, and a National Research Service Award (to C. Fonck). We thank Annett Brandt, Purnima Deshpande, and Ute Roemuss for technical assistance.
Funders:
Funding AgencyGrant Number
Deutsche Forschungsgemeinschaft (DFG)704/3-1
California Tobacco-Related Disease Research ProgramUNSPECIFIED
NIHNS-11756
NIHMH-49176
NIH Predoctoral FellowshipUNSPECIFIED
Subject Keywords:cholinergic excitotoxicity; mouse
Issue or Number:3
Record Number:CaltechAUTHORS:20200422-150959788
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200422-150959788
Official Citation:Knockin mice with Leu9′Ser α4-nicotinic receptors: substantia nigra dopaminergic neurons are hypersensitive to agonist and lost postnatally Sabine Orb, Johannes Wieacker, Cesar Labarca, Carlos Fonck, Henry A. Lester, and Johannes Schwarz Physiological Genomics 2004 18:3, 299-307, https://doi.org/10.1152/physiolgenomics.00012.2004
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:102733
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:23 Apr 2020 14:20
Last Modified:23 Apr 2020 14:20

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