Locomotor hyperactivity and alterations in dopamine neurotransmission are associated with overexpression of A53T mutant human α-synuclein in mice

Erica L. Unger, David J. Eve, Xiomara A. Perez, Dawn K Reichenbach, Yanqun Xu, Michael K. Lee, Anne M. Andrews

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

Abstract

Genetic and biochemical abnormalities associated with α-synuclein are implicated in the etiology of Parkinson's disease (PD). In this study, altered locomotor behavior linked to the expression of mutant or wildtype human α-synuclein was investigated. A53T α-synuclein transgenic (A53T-tg) mice exhibited normal activity at 5 months of age; however, by 7 months, they developed marked hyperactivity that remained evident until 19 months. By contrast, mice expressing human wildtype or A30P mutant α-synuclein showed no locomotor alterations. Hyperactivity in A53T-tg mice was reversed by the D1 receptor antagonist SCH 23390. Furthermore, A53T-tg mice were supersensitive to the D1 receptor agonist SKF 81297 but not to the serotonin1B receptor agonist RU 24969. Hyperactivity in A53T-tg mice was also associated with increased D1 receptor expression in the substantia nigra and decreased dopamine transporter expression in the nucleus accumbens and striatum. Finally, striatal dopamine uptake measured by high-speed chronoamperometry was reduced by 40% in A53T-tg mice. Thus, expression of A53T mutant human α-synuclein in mice results in adult-onset hyperactivity associated with D1 receptor and dopamine transporter-mediated alterations in dopamine neurotransmission.

Original languageEnglish (US)
Pages (from-to)431-443
Number of pages13
JournalNeurobiology of Disease
Volume21
Issue number2
DOIs
StatePublished - Feb 2006
Externally publishedYes

Bibliographical note

Funding Information:
The authors thank Ms. Maggie Burhans (PSU) for her excellent technical assistance with the autoradiography experiments. We also are grateful to Dr. Byron Jones (PSU) for the use of his locomotor activity monitors and critical review of the manuscript and Dr. Allen Mandir (JHU) for his expert advice on activity monitoring. This work was supported by grants from the American Parkinson's Disease Association (AMA), Dystonia Medical Research Foundation (MKL) and National Institutes of Health grants MH64756 (AMA), NS38065 (MKL) and NS38377 (MKL). ELU was supported by a Huck Institute for the Life Sciences graduate fellowship from the Pennsylvania State University.

Keywords

  • Autoradiography
  • Chronoamperometry
  • D1 receptor
  • Dopamine transporter
  • Locomotor activity
  • Parkinson's disease
  • RU 24969
  • SCH 23390
  • SKF 81297
  • α-Synuclein

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