Differential D1 and D2 receptor-mediated effects on immediate early gene induction in a transgenic mouse model of Huntington's disease.
The diminished expression of D1 and D2 dopamine receptors is a well-documented hallmark of Huntington's disease (HD), but relatively little is known about how these changes in receptor populations affect the dopaminergic responses of striatal neurons. Using transgenic mice expressing an N-terminal portion of mutant huntingtin (R6/2 mice), we have examined immediate early gene (IEG) expression as an index of dopaminergic signal transduction. c-fos, jun B, zif268, and N10 mRNA levels and expression patterns were analyzed using quantitative in situ hybridization histochemistry following intraperitoneal administration of selective D1 and D2 family pharmacological agents (SKF-82958 and eticlopride). Basal IEG levels were generally lower in the dorsal subregion of R6/2 striata relative to wild-type control striata at 10-11 weeks of age, a finding in accord with previously reported decreases in D1 and adenosine A2A receptors. D2-antagonist-stimulated IEG expression was significantly reduced in the striata of transgenic animals. In contrast, D1-agonist-induced striatal R6/2 IEG mRNA levels were either equivalent or significantly enhanced relative to control levels, an unexpected result given the reduced level of D1 receptors in R6/2 animals. Understanding the functional bases for these effects may further elucidate the complex pathophysiology of Huntington's disease.
Department of Neurology and Center for Aging, Genetics, and Neurodegeneration, Neurology/B114-2001, Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129-4404, USA.
Boris S
BS
Spektor
David W
DW
Miller
Zane R
ZR
Hollingsworth
Yoshio A
YA
Kaneko
Steven M
SM
Solano
Jennifer M
JM
Johnson
John B
JB
Penney
Anne B
AB
Young
Ruth
R
Luthi-Carter
D000818:Animals; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D017781:Genes, Immediate-Early / Q000187:drug effects / Q000235:genetics*; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
D018491:Dopamine Agonists; D018492:Dopamine Antagonists; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2