Locomotor hyperactivity and alterations in dopamine neurotransmission are associated with overexpression of A53T mutant human alpha-synuclein in mice.
Genetic and biochemical abnormalities associated with alpha-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 alpha-synuclein was investigated. A53T alpha-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 alpha-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 alpha-synuclein in mice results in adult-onset hyperactivity associated with D1 receptor and dopamine transporter-mediated alterations in dopamine neurotransmission.
Unger
Erica L
EL
Huck Institutes for the Life Sciences, The Pennsylvania State University, University Park, 201 Life Sciences Building, University Park, PA 16802, USA.
Eve
David J
DJ
Perez
Xiomara A
XA
Reichenbach
Dawn K
DK
Xu
Yanqun
Y
Lee
Michael K
MK
Andrews
Anne M
AM
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000503:physiopathology*; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D005260:Female; D006801:Humans; D006948:Hyperkinesis / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D009154:Mutation; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; D017447:Receptors, Dopamine D1; D017366:Serotonin Receptor Agonists; D051844:alpha-Synuclein; D004298:Dopamine