Neuronal degeneration in the basal ganglia and loss of pallido-subthalamic synapses in mice with targeted disruption of the Huntington's disease gene.

Huntington's disease (HD) is a progressive neurodegenerative disorder associated with CAG repeat expansion within a novel gene (IT15). We have previously created a targeted disruption in exon 5 of Hdh (Hdhex5), the murine homologue of the HD gene. Homozygotes for the Hdhex5 mutation exhibit embryolethality before embryonic day 8.5, while heterozygotes survive to adulthood and display increased motor activity and cognitive deficits. Detailed morphometric and stereological analyses of the basal ganglia in adult heterozygous mice were performed by light and electron microscopy. Morphometric analyses demonstrated a significant loss of neurons from both the globus pallidus (29%) and the subthalamic nucleus (51%), with a normal complement of neurons in the caudate-putamen and substantia nigra. The ultrastructural appearance of sporadic degenerating neurons in these regions indicated apoptosis. The highest frequency of apoptotic neurons was observed in the globus pallidus and subthalamic nucleus. Stereological analyses in the subthalamic nucleus revealed a significant decrease in the numerical density of symmetric synapses (43%), suggesting a relatively selective loss of inhibitory pallido-subthalamic afferents. Immunohistochemistry using antibodies against enkephalin and substance-P was unremarkable in heterozygotes, indicating a normal complement of enkephalin-immunoreactive striatopallidal afferents and substance-P-immunoreactive striatopeduncular and striatonigral afferents in these animals. These findings show that loss of an intact huntingtin protein is associated with significant morphological alterations in the basal ganglia of adult mice, indicating an important role for this protein during development of the central nervous system.