Haloperidol protects striatal neurons from dysfunction induced by mutated huntingtin in vivo.
Huntington's disease (HD) results from an abnormal polyglutamine extension in the N-terminal region of the huntingtin protein. This mutation causes preferential degeneration of striatal projection neurons. We previously demonstrated, in vitro, that dopaminergic D2 receptor stimulation acted synergistically with mutated huntingtin (expHtt) to increase aggregate formation and striatal death. In the present work, we extend these observations to an in vivo system based on lentiviral-mediated expression of expHtt in the rat striatum. The early and chronic treatment with the D2 antagonist haloperidol decanoate protects striatal neurons from expHtt-induced dysfunction, as analyzed by DARPP-32 and NeuN stainings. Haloperidol treatment also reduces aggregates formation, an effect that is maintained over time. These findings indicate that D2 receptors activation contributes to the deleterious effects of expHtt on striatal function and may represent an interesting early target to alter the subsequent course of neuropathology in HD.
Charvin
Delphine
D
Signalisation Neuronale et Régulations Géniques, Centre National de la Recherche Scientifique, Université Pierre et Marie Curie, UMR 7102, 9 quai Saint Bernard, 75005 Paris, France.
Roze
Emmanuel
E
Perrin
Valérie
V
Deyts
Carole
C
Betuing
Sandrine
S
Pagès
Christiane
C
Régulier
Etienne
E
Luthi-Carter
Ruth
R
Brouillet
Emmanuel
E
Déglon
Nicole
N
Caboche
Jocelyne
J
D000367:Age Factors; D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D002452:Cell Count / Q000379:methods; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006220:Haloperidol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D016086:Lentivirus / Q000502:physiology; D009154:Mutation / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000187:drug effects*; D009687:Nuclear Proteins / Q000235:genetics*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D014150:Antipsychotic Agents; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C497930:Ppp1r1b protein, rat; C033563:haloperidol decanoate; D010751:Phosphopyruvate Hydratase; D006220:Haloperidol