Targeted molecular ablation of D1 dopamine receptor-expressing striatal neurons: a transgenic mouse model of Huntington and other basal ganglia diseases

© 2011 Dr. Hyun Ah KimHuntington disease (HD) involves the loss of both dopamine responsive striatal medium spiny neurons as well as cortical neurons. In early stages of HD, D2 receptor-expressing striatopallidal neurons degenerate and individuals display hyperkinetic involuntary movements. At later stages, D1 receptor-expressing striatonigral neurons degenerate and bradykinesia and limb rigidity become prominent. Rigid-akinetic parkinsonism is the predominant feature of the rare juvenile onset Westphal variant of HD. Other clinical features include gait and orofacial impairments, cognitive deficits, psychosis, and mood and anxiety disorders. To gain a better understanding of the role of D1 receptor-expressing striatonigral neurons in HD and other basal ganglia disorders, a transgenic mouse line with selective ablation of striatal D1 receptor-expressing cells was generated. Mutant mice had reduced bodyweights and displayed motor deficits consistent with a parkinsonian phenotype including bradykinesia, reduced rearing, impaired motor coordination and a short stride-wide based stepping gait. Ethological assessment identified impairments in orofacial movements, and mutant mice displayed reduced anxiety-like behavior but normal spatial working memory. Surprisingly, mutant mice did not display tail suspension limb dystonia. Mutant mice had significant striatal atrophy and astrogliosis, and minor reductions to rostral cortex volume and forebrain weight. The density of dopamine and cyclic AMP-regulated phosphoprotein-32-positive cells was reduced in the striatum but not in the primary motor cortex. The density of striatal D1 receptor-enhanced green fluorescent protein-positive cells was significantly reduced in the dorso-lateral striatum. D1 receptor, dynorphin and substance P mRNA expression was reduced uniformly throughout the entire rostrocaudal extent of the dorsal striatum, while striatal D2 receptor and enkephalin mRNA was upregulated. In addition, comparable changes were noted in the nucleus accumbens, but the extent of these changes was smaller compared with the dorsal striatum. These results suggest that striatopallidal neurons are released from tonic inhibitory control and may be hyperactive. This model recapitulated molecular changes seen in Parkinson disease; including the increased gamma amino butyric acidergic activity in pallidal neurons and increased density of striatal neuropeptide Y and cholinergic interneurons. High performance liquid chromatography analysis revealed reduced dopamine in the striatum and cortex. In addition, the density of dopaminergic neurons in the ventral tegmental area was reduced, whereas neurons in the substantial nigra pars compacta and the density of nigrostriatal terminals in the dorsal striatum were unaffected. These findings suggest that damage to striatonigral neurons is sufficient to produce an extrapyramidal parkinsonian phenotype