Workshop Reports

Several studies have implicated alterations in the responses of excitatory receptors, particularly NMDA receptors, in the pathology of Huntington’s disease (HD). Yet the chain of events that link these disruptions to HD’s primary mutation on the one hand, and to clinical symptoms, on the other, remains unclear. Workshop participants made progress towards generating an integrated view of HD pathology and identifying new directions for future study by analyzing recent results generated by a variety of approaches. They discussed several receptor abnormalities and their potential relationships, including alterations in NMDA receptors’ sensitivity to magnesium, abnormal receptor phosphorylation, disruption of postsynaptic density scaffolds, aberrant IP₃ signaling, and altered receptor trafficking. They also underscored the need to understand the function of wildtype huntingtin, given that loss-of-function effects seem to be important  in HD pathology. To explain the selective vulnerability of striatal neurons, participants noted their unique complement of NMDA receptor subunits—identifying the NR2B subunit as a potentially key determinant of susceptibility—as well as potassium channel subtypes, dopamine receptors and phosphatases. Of particular interest was the convergence of several lines of evidence on dopamine modulation as an important player in HD pathology.

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