Locomotor activity in D2 dopamine receptor-deficient mice is determined by gene dosage, genetic background, and developmental adaptations

Michele A. Kelly, Marcelo Rubinstein, Tamara Phillips, Christina N. Lessov, Sue Burkhart-Kasch, Ge Zhang, James R. Bunzow, Yuan Fang, Gregory A. Gerhardt, David Grandy, Malcolm J. Low

Research output: Contribution to journalArticle

350 Citations (Scopus)

Abstract

Locomotor activity is a polygenic trait that varies widely among inbred strains of mice (Flint et al., 1995). To characterize the role of D2 dopamine receptors in locomotion, we generated F2 hybrid (129/Sv x C57BL/6) D2 dopamine receptor (D2R)-deficient mice by gene targeting and investigated the contribution of genetic background to open-field activity and rotarod performance. Horizontal activity of D2R-/- mice was approximately half that of drug-naive, strain-matched controls but was significantly greater than haloperidol-treated controls, which were markedly hypokinetic. Wild-type 129/SvEv and C57BL/6 mice with functional D2 receptors had greater interstrain differences in spontaneous activity than those among the F2 hybrid mutants. Incipient congenic strains of D2R-deficient mice demonstrated an orderly gene dosage reduction in locomotion superimposed on both extremes of parental background locomotor activity. In contrast, F2 hybrid D2R-/- mice had impaired motor coordination on the rotarod that was corrected in the congenic C57BL/6 background. Wild-type 129/SvEv mice had the poorest rotarod ability of all groups tested, suggesting that linked substrain 129 alleles, not the absence of D2 receptors per se, were largely responsible for the reduced function of the F2 hybrid D2R-/- and D2R+/- mice. Neurochemical and pharmacological studies revealed unexpectedly normal tissue striatal monoamine levels and no evidence for supersensitive D1, D3, or D4 dopamine receptors in the D2R-/- mice. However, after acute monoamine depletion, akinetic D2R+/- mice had a significantly greater synergistic restoration of locomotion in response to SKF38393 and quinpirole compared with any group of D2R+/+ controls. We conclude that D2R-deficient mice are not a model of Parkinson's disease. Our studies highlight the interaction of multiple genetic factors in the analysis of complex behaviors in gene knock-out mice.

Original languageEnglish (US)
Pages (from-to)3470-3479
Number of pages10
JournalJournal of Neuroscience
Volume18
Issue number9
StatePublished - May 1 1998
Externally publishedYes

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Gene Dosage
Locomotion
Dopamine D2 Receptors
Dopamine D4 Receptors
129 Strain Mouse
Dopamine D3 Receptors
Multifactorial Inheritance
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
Quinpirole
Corpus Striatum
Dopamine D1 Receptors
Gene Knockout Techniques
Inbred Strains Mice
Aptitude
Gene Targeting
Haloperidol
mouse DRD2 protein
Genetic Background
Inbred C57BL Mouse
Knockout Mice

Keywords

  • 129/SvEv mice
  • C57BL/6 mice
  • D2 dopamine receptor
  • Dopamine
  • Gene knock-out mice
  • Genetics
  • Locomotor activity
  • Rotarod

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Kelly, M. A., Rubinstein, M., Phillips, T., Lessov, C. N., Burkhart-Kasch, S., Zhang, G., ... Low, M. J. (1998). Locomotor activity in D2 dopamine receptor-deficient mice is determined by gene dosage, genetic background, and developmental adaptations. Journal of Neuroscience, 18(9), 3470-3479.

Locomotor activity in D2 dopamine receptor-deficient mice is determined by gene dosage, genetic background, and developmental adaptations. / Kelly, Michele A.; Rubinstein, Marcelo; Phillips, Tamara; Lessov, Christina N.; Burkhart-Kasch, Sue; Zhang, Ge; Bunzow, James R.; Fang, Yuan; Gerhardt, Gregory A.; Grandy, David; Low, Malcolm J.

In: Journal of Neuroscience, Vol. 18, No. 9, 01.05.1998, p. 3470-3479.

Research output: Contribution to journalArticle

Kelly, MA, Rubinstein, M, Phillips, T, Lessov, CN, Burkhart-Kasch, S, Zhang, G, Bunzow, JR, Fang, Y, Gerhardt, GA, Grandy, D & Low, MJ 1998, 'Locomotor activity in D2 dopamine receptor-deficient mice is determined by gene dosage, genetic background, and developmental adaptations', Journal of Neuroscience, vol. 18, no. 9, pp. 3470-3479.
Kelly, Michele A. ; Rubinstein, Marcelo ; Phillips, Tamara ; Lessov, Christina N. ; Burkhart-Kasch, Sue ; Zhang, Ge ; Bunzow, James R. ; Fang, Yuan ; Gerhardt, Gregory A. ; Grandy, David ; Low, Malcolm J. / Locomotor activity in D2 dopamine receptor-deficient mice is determined by gene dosage, genetic background, and developmental adaptations. In: Journal of Neuroscience. 1998 ; Vol. 18, No. 9. pp. 3470-3479.
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