Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 41, Pages 15991-15996Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0807635105
Keywords
dopaminergic systems; gene rescue; lentiviral vector; RNAi
Categories
Funding
- Fondation pour a Recherche Medicale and Region Ile-de-France
- Institut Pasteur
- Unite de Recherche Associee [2182]
- Centre National de la Recherche Scientifique
- College de France
- Association pour la Recherche sur le Cancer
- French National Science Foundation
- Fondo de Investigaciones Sanitarias [PI070709]
- Ministerio de Ciencia y Tecnologia [SAF2007-64062]
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Acetylcholine (ACh) is a known modulator of the activity of dopaminergic (DAergic) neurons through the stimulation of nicotinic ACh receptors (nAChRs). Yet, the subunit composition and specific location of nAChRs involved in DA-mediated locomotion remain to be established in vivo. Mice lacking the beta 2 subunit of nAChRs (beta 2KO) display striking hyperactivity in the open field, which suggests an imbalance in DA neurotransmission. Here, we performed the selective gene rescue of functional beta 2*-nAChRs in either the substantia nigra pars compacta (SNpc) or the ventral tegmental area (VTA) of beta 2KO mice. SNpc rescued mice displayed normalization of locomotor activity, both in familiar and unfamiliar environments, whereas restoration in the VTA only rescued exploratory behavior. These data demonstrate the dissociation between nigrostriatal and mesolimbic beta 2*-nAChRs in regulating unique locomotor functions. In addition, the site-directed knockdown of the beta 2 subunit in the SNpc by RNA interference caused hyperactivity in wild-type mice. These findings highlight the crucial interplay of nAChRs over the DA control of spontaneous locomotion.
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