Abstract
Abnormal involuntary movements and cognitive impairment represent the classical clinical symptoms of Huntington's disease (HD). This genetic disorder involves degeneration of striatal spiny neurons, but not striatal large cholinergic interneurons, and corresponds to a marked decrease in the activity of mitochondrial complex II [succinate dehydrogenase (SD)] in the brains of HD patients. Here we have examined the possibility that SD inhibitors exert their toxic action by increasing glutamatergic transmission. We report that SD inhibitors such as 3-nitroproprionic acid (3-NP), but not an inhibitor of mitochondrial complex I, produce a long-term potentiation of the NMDA-mediated synaptic excitation (3-NP-LTP) in striatal spiny neurons. In contrast, 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-activated protein kinase extracellular signal-regulated kinase and is critically 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 in the regional and cell type-specific neuronal death observed in HD.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Calcium Channel Blockers / pharmacology
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Chelating Agents / pharmacology
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Corpus Striatum / metabolism*
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Dopamine / metabolism*
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Electric Stimulation
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Electron Transport Complex I
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Electron Transport Complex II
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Enzyme Inhibitors / pharmacology
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Excitatory Amino Acid Agonists / pharmacology
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Excitatory Postsynaptic Potentials / drug effects
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Excitatory Postsynaptic Potentials / physiology
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Huntington Disease / enzymology
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Huntington Disease / metabolism*
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In Vitro Techniques
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Interneurons / drug effects
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Interneurons / metabolism
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Long-Term Potentiation / drug effects
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Long-Term Potentiation / physiology*
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Membrane Potentials / drug effects
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Methylmalonic Acid / pharmacology
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Mice
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Mitochondria / drug effects
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Mitochondria / enzymology*
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Multienzyme Complexes / antagonists & inhibitors
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Multienzyme Complexes / metabolism*
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N-Methylaspartate / metabolism
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NADH, NADPH Oxidoreductases / antagonists & inhibitors
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Neurons / drug effects
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Neurons / metabolism
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Nitro Compounds
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Oxidoreductases / antagonists & inhibitors
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Oxidoreductases / metabolism*
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Propionates / pharmacology
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Pyramidal Cells / drug effects
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Pyramidal Cells / metabolism
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Rats
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Rats, Wistar
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Succinate Dehydrogenase / antagonists & inhibitors
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Succinate Dehydrogenase / metabolism*
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Synaptic Transmission / drug effects
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Synaptic Transmission / physiology*
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Uncoupling Agents / pharmacology
Substances
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Calcium Channel Blockers
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Chelating Agents
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Enzyme Inhibitors
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Excitatory Amino Acid Agonists
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Multienzyme Complexes
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Nitro Compounds
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Propionates
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Uncoupling Agents
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N-Methylaspartate
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Methylmalonic Acid
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Oxidoreductases
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Electron Transport Complex II
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Succinate Dehydrogenase
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NADH, NADPH Oxidoreductases
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Mitogen-Activated Protein Kinase Kinases
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Electron Transport Complex I
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3-nitropropionic acid
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Dopamine