Huntington's disease (HD), a dominantly inherited neurodegenerative disease, is 
defined by its genetic cause, a CAG-repeat expansion in the HTT gene, its motor 
and psychiatric symptomology and primary loss of striatal medium spiny neurons 
(MSNs). However, the molecular mechanisms from genetic lesion to disease 
phenotype remain largely unclear. Mouse models of HD have been created that 
exhibit phenotypes partially recapitulating those in the patient, and 
specifically, cortico-striatal disconnectivity appears to be a shared pathogenic 
event shared by HD mouse models and patients. Molecular studies have begun to 
unveil converging molecular and cellular pathogenic mechanisms that may account 
for cortico-striatal miscommunication in various HD mouse models. Systems 
biological approaches help to illuminate synaptic molecular networks as a nexus 
for HD cortio-striatal pathogenesis, and may offer new candidate targets to 
modify the disease.