Ample evidence suggests a critical role for NMDARs in initiating MSN dysfunction and death in HD. The expression of mhtt may produce changes in NMDAR composition, trafficking, and function. Additionally, it may affect neuronal responses to NMDAR activation, particularly those downstream of and dependent upon Ca2+ signalling and mitochondrial pathways (Figure 2.1). Evidence from cellular and animal models of HD suggests that these changes in turn can alter synaptic function and enhance the susceptibility of MSNs to NMDAR-mediated excitotoxicity in a polyQ length-dependent fashion. In summary, NMDARs may play a prominent role in the pathology of HD. The complexity of the interactions between mhtt and NMDARs presents a number of possible targets for effective and selective therapies.
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