Select Page


Huntington’s disease (HD) is a lethal autosomal dominant neurodegenerative disease that leads to deficits in motor control and cognitive/psychiatric functions. Chorea, a loss of motor control that is characteristic of HD physical symptoms, is thought to reflect a dysfunction of the indirect pathway (IP) drive arising from a deficit of striatal output to globus pallidus (GP), which in turn innervates subthalamic nucleus (STN). Due to the inhibitory GABAergic projections from GP to STN, it is expected that an increase in GP activity would lead to a decrease in STN neuronal discharge. Electrophysiological studies in basal ganglia slices from symptomatic transgenic BACHD rats carrying full length mutant huntingtin has shown increased GP and decreased STN firing consistent with this hypothesis1.

We have now evaluated spontaneous single unit discharges in GP and STN in-vivo, in heterozygous (HET) and homozygous (HOM) z_Q175 mice, a knock-in mouse model of HD which carries either one wildtype and one mutant htt allele containing an expanded CAG repeats (HET), or two mutant Htt alleles (HOM)2,3. Six month-old HET, HOM and WT littermate mice were anesthetized using urethane, and extracellular single unit spikes were recorded in their GP or STN region. Expression of mutant Htt appeared to alter the firing rate of STN neurons, as firing rates in HET and HOM mice were lower than their WT littermate. Our data also suggest a gene dosage effect on decreasing firing rate in STN neurons, since the probability of detecting spontaneously active units in Homo mice is significantly lower than Het. in contrast to STN, expression of mutant Htt has no effect on GP neurons firing rate.