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S. ZHONG, G. TOMBAUGH, S.BENT, L. MRZLJAK, V. BEAUMONT, A. GHAVAMI

Chorea in Huntington’s disease(HD) patients has been proposed to arise predominantly from indirect pathway (IP) dysfunction. D2-expressing striatal medium spiny neurons (MSN) giving rise to IP projections appear more vulnerable to mutant huntingtin (mHtt) insult. Impaired IP output would be expected to alter the activity of downstream nuclei, particularly theglobuspallidus (GP) which receives strong inhibitory input from the IP, and the subthalamic nucleus (STN), which receives strong inhibitory input from the GP. We have tested this hypothesisin a full length BACHD rat model, by recording firing rates from GP and STN in vivo at a behaviorally symptomatic age. The feasibility of simultaneous dual recordings from GP and STN was first assessed in anesthetized Sprague-Dawley rats. Using 5 month old WT rats (n=18), firing rates of GP and STN neurons were 19.68 ± 2.3 Hz and 7.4±1.65 Hz, respectively. Both GP and STN neurons could be classified into three subtypes of neuronal firing patterns: burst, regularand irregular. In GP, 39% of the neurons discharged regularly, 50% fired irregularly, and 11% fired in a bursting pattern. In STN, 11% of the neurons discharged regularly, 39% showed irregular firing patterns, and 50% exhibited a bursting pattern. In several recordings, we observed dynamic changes in unit firing that we defined as either in-phase or out-of-phase consistent with previous reports. Dual single unit recordings from GP and STN of 8-10 month transgenic BACHD and WT rats revealed the same 3 firing patterns. In BACHD rats, mean firing rates showed a non-significant increase in GP (P=0.22) and a significant decrease in STN (P<0.05) relative to age-matched WT littermates.The firing rates for GP were 20.26 ± 2.96 Hz in WT rats and 25.45± 2.82 Hz in BACHD rats. The firing rates for STN were 10.87 ± 1.96 Hz in WT rats and 5.18 ±1.85 Hz in BACHD rats. Our data provide evidence that mHttinfluences the firing properties of neurons in the pallidosubthalamic pathway in rodent HD models similar to changes reported in HD patients. A dual recording approach in HD rodents may be a useful model for assessing compounds that modify abnormal activity of the indirect pathway.