Neocortical expression of mutant huntingtin is not required for alterations in striatal gene expression or motor...

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disease caused by an expanded polyglutamine tract in the ubiquitously expressed huntingtin protein. Clinically, HD is characterized by motor, cognitive and psychiatric deficits. Striking degeneration of the striatum is observed in HD with the medium spiny neurons (MSNs) being the most severely affected neuronal subtype. Dysfunction of MSNs is marked by characteristic changes in gene expression which precede neuronal death. The ubiquitous expression of the huntingtin protein raises the question as to whether the selective vulnerability of the MSN is cell-autonomous, non-cell-autonomous, or a combination thereof. In particular, growing evidence suggests that abnormalities of the cortex and corticostriatal projections may be primary causes of striatal vulnerability. To examine this issue, we developed transgenic mice that, within the forebrain, selectively express a pathogenic huntingtin species in the MSNs, specifically excluding the neocortex. These mice develop a number of abnormalities characteristic of pan-cellular HD mouse models, including intranuclear inclusion bodies, motor impairment, and changes in striatal gene expression. As this phenotype develops in the presence of normal levels of brain-derived neurotrophic factor and its major striatal receptor, tropomyosin-related kinase B, these data represent the first demonstration of in vivo cell-autonomous transcriptional dysregulation in an HD mouse model. Furthermore, our findings suggest that therapies targeted directly to the striatum may be efficacious at reversing some of the molecular abnormalities present in HD.