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1Psychogenics Inc, Tarrytown, NY; 2Translational Biol., CHDI Mgmt. / CHDI Fndn., Los Angeles, CA

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder resulting from an extended number of CAG repeats in the Huntingtin (Htt) gene, for which no disease-modifying therapy is currently available. HD comprises several cognitive and affective symptoms, as well as uncontrolled movement (chorea), which have been hypothesized to arise from a preferential vulnerability of indirect pathway spiny projection neurons (iSPNs) preceding dysfunction of the direct pathway SPNs (dSPNs) in the striatum. In order to characterize this possible imbalance, we performed in vitro brain slice whole patch-clamp recordings from the Q175 heterozygous knock-in HD mouse model expressing GFP under the control of the D2 receptor promoter to identify dSPNs (GFP-negative) and iSPNs (GFP-positive). We asked to what extent alterations in intrinsic and synaptic properties in Q175 mice were selectively affected in each SPN subtype. Using whole-cell path clamp, both dSPNs and iSPNs from Q175 6-month old mice showed elevated membrane resistance and reduced rheobase current, consistent with previous reports of SPN hyperexcitability in mouse models of HD. Membrane resistance and rheobase in both dSPN and iSPNs from 2-month old Q175 mice did not significantly differ from Wild-type (WT) dSPN and iSPNs respectively, suggesting that deficits in SPN excitability emerged largely in parallel in each subtype. Analysis of mEPSC properties in SPNs revealed a significant decrease in mEPSC frequency only in iSPNs from 6-month old Q175 mice, with no genotypic differences in mEPSC amplitude in either cell type. Amplitude and frequency of mEPSCs were unchanged in 2-month old Q175 mice compared to WT. Finally, we examined LTP at corticostriatal synapses in 6-month old mice using a Hebbian protocol consisting of 4 trains of 100 Hz presynaptic stimulation paired with postsynaptic depolarization. We found that corticostriatal LTP was decreased in dSPNs, while LTP expression in iSPNs was unchanged. Altogether, these results suggest that HD progression is not equally expressed in the indirect and direct pathways. Additional studies are, however, necessary to better understand such differential impairment.