Purkinje cell dysfunction and loss in a knock-in mouse model of Huntington Disease

Huntington Disease (HD) is an autosomal dominant neurological disorder characterized by motor, psychiatric and cognitive disturbances. Recent evidence indicates that the viability and function of cerebellar Purkinje cells (PCs) are compromised in an aggressive mouse model of HD. Here we investigate whether this is also the case in the HdhQ200 knock-in mouse model of HD. Using quantitative-real time-PCR and immunofluorescence, we observed a loss of the PC marker and calcium buffer calbindin in 50 week-old symptomatic mice. Reductions were also observed in parvalbumin and glutamic acid decarboxylase protein expression, most markedly in the molecular cell layer. Stereological analysis revealed an overall reduction in the PC population in HdhQ200/Q200 mice by nearly 40%, and loose patch electrophysiology of remaining PCs indicated a reduction in firing rate in HD mice compared to control littermates. Taken together, these data demonstrate that PC survival and function are compromised in a mouse model of adult-onset HD and suggest that further experiments should investigate the contribution of PC death and dysfunction to HD-associated motor impairment.

► PCs are dysfunctional in the R6/2 model of juvenile HD evidenced by lost transcripts, protein, and cell number. ► Similar alterations are seen in the HdhQ200 knock-in model of HD. ► Electrophysiological abnormalities are present in PCs of homozygous knock-in mice. ► Intranuclear inclusions are present within PCs of homozygous knock-in mice. ► Further experiments should determine PC involvement in adult HD-associated motor impairments.