Severe deficiencies in dopamine signaling in presymptomatic Huntington's disease mice

摘要

In Huntington's disease (HD), mutation of huntingtin causes selective neurodegeneration of dopaminoceptive striatal medium spiny neu- rons. 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 dopa- mine 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 D1 dopamine/DARPP-32 signaling cascade. These presymptomatic defects may contribute to HD pathology.