Inhibition of mitochondrial complex II induces a long-term potentiation ofNMDA-mediated synaptic excitation in the striatum requiring endogenous dopamine

Abnormal involuntary movements and cognitive impairment represent the class ical clinical symptoms of Huntington's disease (HD). This genetic disorder involves degeneration of striatal spiny neurons, but not striatal large cho linergic interneurons, and corresponds to a marked decrease in the activity of mitochondrial complex II [succinate dehydrogenase (SD)] in the brains o f HD patients. Here we have examined the possibility that SD inhibitors exe rt their toxic action by increasing glutamatergic transmission. We report t hat SD inhibitors such as 3-nitroproprionic acid (3-NP), but not an inhibit or of mitochondrial complex I, produce a long-term potentiation of the NMDA -mediated synaptic excitation (3-NP-LTP) in striatal spiny neurons. In cont rast, these inhibitors had no effect on excitatory synaptic transmission in striatal cholinergic interneurons and pyramidal cortical neurons. 3-NP-LTP involves increased intracellular calcium and activation of the mitogen-act ivated protein kinase extracellular signal-regulated kinase and is critical ly dependent on endogenous dopamine acting via D2 receptors, whereas it is negatively regulated by D1 receptors. Thus 3-NP-LTP might play a key role i n the regional and cell type-specific neuronal death observed in HD.