Striatal neuronal apoptosis is preferentially enhanced by NMDA receptor activation in YAC transgenic mouse model of Huntington disease

• Main Authors: Jacqueline Shehadeh, Herman B. Fernandes, Melinda M. Zeron Mullins, Rona K. Graham, Blair R. Leavitt, Michael R. Hayden, Lynn A. Raymond
• Format: Article
• Language: English
• Published: Elsevier 2006-02-01
• Series: Neurobiology of Disease
• Subjects: Apoptosis; Mitochondria; Primary neuronal culture; Excitotoxicity
• Online Access: http://www.sciencedirect.com/science/article/pii/S0969996105002172

Huntington disease (HD), caused by expansion >35 of a polyglutamine tract in huntingtin, results in degeneration of striatal medium spiny neurons (MSNs). Previous studies demonstrated mitochondrial dysfunction, altered intracellular calcium release, and enhanced NMDAR-mediated current and apoptosis in cellular and mouse models of HD. Here, we exposed cultured MSNs from YAC transgenic mice, expressing full-length human huntingtin with 18, 72, or 128 repeats, to a variety of apoptosis-inducing compounds that inhibit mitochondrial function or increase intracellular calcium, and assessed apoptosis 24 h later. All compounds produced a polyglutamine length-dependent increase in apoptosis, but NMDA produced the largest potentiation in apoptosis of YAC72 and YAC128 versus YAC18 MSNs. Moreover, reduction of NMDAR-mediated current and calcium influx in YAC72 MSNs to levels seen in wild-type reduced NMDAR-mediated apoptosis proportionately to wild-type levels. Our results suggest that increased NMDAR signaling plays a major role in enhanced excitotoxic MSN death in this HD mouse model.