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1PsychoGenics, Inc., Paramus, NJ, USA;
2Translational Biology, CHDI Mgmt. / CHDI Foundation, Los Angeles, CA

Changes in corticostriatal neurotransmission have been identified as an early pathophysiological event observed in Huntington’s disease (HD), and model organisms have been a critical tool in furthering our understanding of these disease-driven processes. Examination of the Q175 mouse model of HD has uncovered changes in intrinsic membrane properties and excitability of both direct (D1 receptor-expressing) and indirect (D2 receptor-expressing) pathway medium spiny striatal projection neurons (SPNs). We have extended this work by probing the function of the direct and indirect corticostriatal pathways, using electrical stimulation of brain slices obtained from lines of Q175 mice expressing GFP in either D1-expressing (D1-GFP) or D2-expressing (D2-GFP) SPNs. We used three independent measures to assess excitatory presynaptic function: namely i) input-output relationship; ii) the relative size of the readily releasable pool (RRP) of synaptic vesicles; and iii) evoked Sr2+-mediated asynchronous release from cortical afferents. We found that glutamatergic corticostriatal transmission was decreased in indirect pathway (D2-GFP) SPNs, but was similar to WT in the direct (D1) pathway at the same age. This impairment in indirect pathway transmission was observed at several stimulus intensities. Paired pulse ratios at 25 ms and 50 ms intervals were unaffected in Q175het animals, suggesting that release probability was largely unaffected. Estimates of RRP size from a single stimulus train suggested a significant reduction in the number of vesicles available for release in indirect pathway corticostriatal terminals, while direct pathway terminals in Q175het slices were not significantly different from WT. We also observed a decrease in the frequency of asynchronous EPSC events following stimulation of indirect pathway Q175het corticostriatal afferents compared to WT, while no such deficit was observed in the direct pathway. These data are consistent with a corticostriatal deficit in neurotransmission in the indirect pathway of 6-month old Q175het mice, suggesting a potential pathway-specific mechanism of corticostriatal dysfunction.