Figure 6.

A general model for the main excitotoxic events in the various YAC HD models. Previous research established that enhanced NMDAR activation (step 1) leads to elevated peak cytosolic Ca²⁺ (step 2) and subsequent mitochondrial depolarization (step 3), caspase activation (step 4), and apoptosis (step 5) in YAC46 and YAC72 MSNs. In the YAC128 mouse model, steps 1 and 2 do not appear to play a role in the enhancement of apoptosis for YAC128 versus WT MSNs. The key excitotoxic step augmented in YAC128 MSNs occurs at the level of the mitochondria (step 3), but is still dependent on NMDAR activation. Thus, the increased sensitivity to NMDA-induced toxicity occurs at a later point in the sequence of events leading to apoptotic death in YAC128 compared with YAC72 MSNs. Delayed recovery from NMDA-induced Ca²⁺ loads in YAC128 MSNs may also serve to enhance calpain activity levels after intense NMDAR activity.