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H. LIN, S. ZHONG, S. BENT, H. S. HAIN, V. BEAUMONT, A. GHAVAMI

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 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 normal Htt allele and one mutant htt allele with an expanded CAG tract (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 GP or STN. The firing rate of STN neurons appeared to be more sensitive to the presence of mHtt, with lower firing rates in HET and HOM mice compared to WT counterparts; however there was no change in mean firing rate difference found for GP neurons between WT and HET. The lack of rate difference in GP could either stem from less sensitivity of GP neurons to IP dysfunction, or could be due to GP heterogeneity in firing rate and pattern that makes detection of abnormalities in single unit activity harder in GP than STN. Alternatively, an impairment of the hyperdirect pathway (excitatory glutamatergic cortico-STN projection) could result in a hypoactive STN with minimum impact in GP activity, at least during the early stage of HD neurodegeneration in the z_Q175 mouse model.

1. Zhong et al. (2013). Evaluation of MP-10, a PDE10 inhibitor, on BACHD transgenic rats using dual recording of single units in Globus Pallidus and Subthalamic nucleus. SFN poster 2013.
2. Heikkinen T et al. (2012) PLoS ONE
3. Menalled LB et al. (2012) PLoS ONE
(This study was funded by CHDI Foundation.)