Figure 8.

Glutamate and dopamine signaling pathways act synergistically to induce Ca ²⁺overload and apoptosis of HD MSNs. Dopamine (Dop) released from midbrain dopaminergic neurons (Gerfen, 1992) stimulates D₁-class and D₂-class DARs, which are abundantly expressed in MSNs (Surmeier et al., 1996). D₁-class DARs are coupled to G_s/olf, activation of adenyl cyclase, and cAMP production (Missale et al., 1998). PKA potentiates glutamate-induced Ca ²⁺signals by facilitating activity of NMDAR (Levine et al., 1996; Flores-Hernandez et al., 2002) and InsP₃R1 (Tang et al., 2003a; Tang and Bezprozvanny, 2004). In HD MSNs, NR2B- and InsP₃R1-mediated Ca²⁺ signaling is further facilitated by Htt ^exp (Zeron et al., 2002, 2004; Tang et al., 2003b, 2005). As a result, simultaneous activation of glutamate and dopamine receptors leads to cytosolic and mitochondrial Ca ²⁺overload in HD MSNs. The mitochondrial Ca ²⁺handling is further destabilized by direct association of Htt ^exp with mitochondria (Mito) (Panov et al., 2002; Choo et al., 2004). Once mitochondrial Ca ²⁺ storage capacity is exceeded, mitochondrial permeability transition pore (MPTP) opens, leading to release of cytochrome c into the cytosol and activation of caspases 9 and 3, which leads to progression of apoptosis, MSN degeneration, and HD. The model is supported by the ability of blockers (shown in red) to protect YAC128 MSNs from dopamine/glutamate-induced apoptosis in our in vitro experiments. The blockers that were effective in in vitro experiments are as follows: D₁-class DAR blocker SCH23390; NMDAR blocker (+)-MK801 and NR2B-specific blocker ifenprodil; mGluR1/5-specific blockers MPEP and CPCCOEt; and membrane-permeable InsP₃R1 blockers 2-APB and enoxaparin (Enox). Also shown is a clinically relevant NMDAR antagonist, memantine (MMT), which protects YAC128 MSNs from glutamate-induced apoptosis (Wu et al., 2006), and a clinically relevant dopamine pathway inhibitor, TBZ, which demonstrated efficacy in the whole-animal experiments with a YAC128 HD mouse model as described in Results. PLC, Phospholipase C.