S. ZHONG, G. TOMBAUGH, L. MRZLJAK, V. BEAUMONT, C. SCHMIDT, M. ZALESKA, C. CHANG, A. GHAVAM
Chorea in Huntington’s disease (HD) patients might be due in part to a dysfunction of the indirect pathway (IP) of the basal ganglia. D2-expressing striatal medium spiny neurons (MSN), giving rise to IP projections, appear more vulnerable to expression of mutant huntingtin (mHtt). A consequence of the preferential loss of striato-external pallidal (GPe) projections in HD patients would be expected to result in increased GPe firing rate, reduced STN firing rate, reduced activity of GPi, and ultimately overactivity of the thalamus, resulting in chorea. Previous studies in the mouse BACHD model (6 month old), reported an age-dependent increase in mean firing rate of GP neurons and decrease in the mean firing rate of STN neurons in vitro (D.J. Surmeier, Northwestern Univ.) and in vivo (James Tepper, Rutgers Univ.). The current study, using dual simultaneously recording from GP and STN, demonstrated that comparable alterations in firing rates was also detected in 8 to 15 months old BACHD full length transgenic rats. Mean spontaneous firing rates showed a significant increase in GPe (22.2±2.0 Hz in WT vs. 30.4±2.5 Hz in BACHD, P<0.02) and a significant decrease in STN (10.8±1.1 Hz in WT vs. 6.7±1.0 Hz in BACHD, P<0.005). The phosphodiesterase 10 (PDE10) is highly expressed within dopaminoreceptive MSNs of the striatum and PDE10 inhibitors have been viewed as a potential treatment for schizophrenia. To provide a rationale for developing PDE10 inhibitors as a therapy for HD, we evaluated whether MP-10, a specific and potent PDE10 inhibitor, would be able to reverse the altered firing rate observed in BACHD rat. A single bolus IV injection of MP-10 at all doses studied (0.18, 0.52, and 1.5 mg/kg) produced a clear increase in the firing rate of STN neurons in both WT and TG rats. Surprisingly, MP-10 effect on the GP firing rate was modest. PK/PD relationship was studied by collecting blood samples at 5, 30, 60, and 120 minutes after compound administration. The earliest effect on firing rates was observed at 3 to 5 minutes post MP-10 administration, which may reflect the time needed for cAMP/cGMP to reach a critical level. The magnitude of firing rate increase in STN was not dramatically different across doses, but the 0.52 and 1.5mg/kg doses produced longer lasting effects than the 0.18mg/kg dose. Our data provide evidence that are complementary to the prevailing hypothesis in HD patients; expression of mHtt in rats alters the firing properties of neurons in the “indirect” pallidosubthalamic pathway. MP-10 restored the low STN firing rates in BACHD rats, which is consistent with a potential therapeutic action of PDE10 inhibitors for the treatment of HD.