, 2007) at an age when subtle gait abnormalities are visible (Lin et al., 2001). These observations may be indicative of progressive compensation to heightened baseline Ca2+ levels in aged HD mouse striatal neurons, perhaps also mediating QA resistance. Mitochondrial biogenesis deficiencies may be a contributing factor, as PGC-1α, a positive regulator of mitochondrial biogenesis, is reduced in both human HD samples and 12 month HdhQ140 striatal MSNs (but is elevated in interneurons) (Cui et al., 2006). Disturbances BAY 73-4506 of mitochondria in HD are perhaps not surprising, given neuronal ATP

requirements, and the data demonstrate that mHTT can perturb mitochondrial calcium sensitivity. The hypersensitivity

of MSNs to a mitochondrial poison, combined with the mouse mitochondrial perturbations and a general metabolic deficit in HD patients, strongly suggest that both CNS and peripheral symptoms of HD are influenced by altered mitochondrial function. Many motor and behavioral symptoms in HD arise from the massive loss of MSNs, and the motor symptoms that acute 3-NP and QA toxicity produce are reminiscent of advanced HD. However, many mouse models of HD demonstrate almost no neuronal death. That neurons can be intact but still clearly malfunctioning, combined with the cognitive and memory deficits seen in most patients, suggests that synaptic abnormalities may be significant in HD pathology.

Disturbances in long-term potentiation (LTP) and long-term depression (LTD) are presented as evidence of a synaptic plasticity dysfunction, Stem Cell Compound Library and such abnormal responses to LTP and LTD are seen in almost all mouse HD models. Asymptomatic heterozygous HdhQ72-80 mice displayed impaired hippocampal LTP between 8 and 14 months of age (Usdin et al., 1999), as did YAC46 and YAC72 by 6 months (Hodgson et al., 1999); R6/2 averaged from 5 weeks to endstage (Murphy et al., Thiamine-diphosphate kinase 2000). HdhQ92 and HdhQ111 displayed impairment at 2 months old and 4–6 months old, respectively, and HdhQ140 mice at only 8 weeks old (Simmons et al., 2009). LTD was also abnormal in R6/2 s (Murphy et al., 2000) and R6/1 s (Cummings et al., 2007 and Cummings et al., 2006). LTP or LTD deficits have not been reported in BACHD mice, but reduction in high-amplitude mEPSCs of MSNs at 6 months (Gray et al., 2008), as well as cortical synaptic alterations at the same age (Spampanato et al., 2008) demonstrate some corticostriatal circuitry impairment in this strain as well. As impaired performance at cognitive tasks such as the Morris water maze or T maze is seen in R6/2 s (Lione et al., 1999) and YAC128 (Van Raamsdonk et al., 2005c) animals, as well as somatosensory associative memory problems in R6/1 s (Cybulska-Klosowicz et al., 2004), the LTP and LTD impairments probably represent behaviorally relevant plasticity deficits.