Severe deficiencies in dopamine signaling in presymptomatic Huntington's disease mice.
In Huntington's disease (HD), mutation of huntingtin causes selective neurodegeneration of dopaminoceptive striatal medium spiny neurons. Transgenic HD model mice that express a portion of the disease-causing form of human huntingtin develop a behavioral phenotype that suggests dysfunction of dopaminergic neurotransmission. Here we show that presymtomatic mice have severe deficiencies in dopamine signaling in the striatum. These include selective reductions in total levels of dopamine- and cAMP-regulated phosphoprotein, M(r) 32 kDA (DARPP-32) and other dopamine-regulated phosphoprotein markers of medium spiny neurons. HD mice also show defects in dopamine-regulated ion channels and in the D(1) dopamine/DARPP-32 signaling cascade. These presymptomatic defects may contribute to HD pathology.
Bibb
J A
JA
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10021-6399, USA. bibbj@rockvax.rockefeller.edu
Yan
Z
Z
Svenningsson
P
P
Snyder
G L
GL
Pieribone
V A
VA
Horiuchi
A
A
Nairn
A C
AC
Messer
A
A
Greengard
P
P
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000502:physiology*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D006801:Humans; D006816:Huntington Disease / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins / Q000032:analysis / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D017447:Receptors, Dopamine D1 / Q000502:physiology; D011963:Receptors, GABA-A / Q000502:physiology
D001552:Benzazepines; D015220:Calcium Channels; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D011963:Receptors, GABA-A; C067113:SK&F 81297; D004298:Dopamine