Regulation of effector pathways involved in protection from NMDA receptor-induced excitotoxicity in a mouse model of Huntington's disease
I started this thesis with the hypothesis that Huntington's disease is the result of an increased NMDAR-induced excitotoxicity resulting from long term changes in NMDAR effector pathways and that the neuroprotective agent nicotine would delay toxicity, symptoms and premature death. Many drugs reported to have neuroprotective activity have been shown to decrease symptoms and/or prolong life in mouse models of Huntington's disease. We show in chapter 2 that oral nicotine treatment, reported to be neuroprotective in many other in vivo models to be discussed later, was ineffective in producing significant reduction of symptoms or prolonging life in a mouse model of Huntington's disease. Since the neuroprotective agent nicotine had no effect and the mouse models of Huntington's disease show little neuronal death, we studied the neuronal death associated with NMDA receptor-induced excitotoxicity in a mouse model of Huntington's disease. Other transgenic mouse models have shown decreases, increases, or no effect with respect to NMDA receptor-induced excitotoxicity. In Chapter 3, we report protection from NMDA receptor-induced excitotoxicity in the striata of symptomatic N171-82Q mice, a model of Huntington's disease in which an N-terminal portion of the mutant huntingtin protein containing the extended polyglutamine region associated with the disease is expressed. Chapter 4 and 5 examine the regulation of known effector pathways of NMDA receptor excitotoxicity that may be responsible for the protection observed in the N171-82Q mouse model. We observe decreases in proteins of the neuronal nitric oxide synthase pathway. We also observe decreases in dopamine D1 receptors with a decrease in the associated phosphorylation of the NR1 subunit of the NMDA receptor and an increase in membrane-association of the antiapoptotic phosphatidylinositol-3 kinase, which was recently reported to compete with dopamine D1 receptors for a binding site on NR1. All of these changes would be predicted to protect these neurons from NMDA receptor excitotoxicity. A modified hypothesis is that the “protective” protein changes affecting the two primary inputs to the striatum, glutamatergic and dopaminergic, may be causing a functional deficit responsible for some of the symptoms associated with the disease.