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

Paolo Calabresi, Paolo Gubellini, Barbara Picconi, Diego Centonze, Antonio Pisani, Paola Bonsi, Paul Greengard, Robert A. Hipskind, Emiliana Borrelli, Giorgio Bernardi

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)5110-5120
Number of pages11
JournalJournal of Neuroscience
Volume21
Issue number14
Publication statusPublished - Jul 15 2001

Fingerprint

Corpus Striatum
Long-Term Potentiation
N-Methylaspartate
Succinate Dehydrogenase
Dopamine
Huntington Disease
Acids
Dyskinesias
Interneurons
Cholinergic Agents
Toxic Actions
Neurons
Inborn Genetic Diseases
Pyramidal Cells
Extracellular Signal-Regulated MAP Kinases
Brain Diseases
Mitogen-Activated Protein Kinases
Synaptic Transmission
Calcium
Inhibition (Psychology)

Keywords

  • D2 dopamine receptors
  • Excitotoxicity
  • Huntington's disease
  • Striatum
  • Succinate dehydrogenase
  • Synaptic plasticity

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Inhibition of mitochondrial complex II induces a long-term potentiation of NMDA-mediated synaptic excitation in the striatum requiring endogenous dopamine. / Calabresi, Paolo; Gubellini, Paolo; Picconi, Barbara; Centonze, Diego; Pisani, Antonio; Bonsi, Paola; Greengard, Paul; Hipskind, Robert A.; Borrelli, Emiliana; Bernardi, Giorgio.

In: Journal of Neuroscience, Vol. 21, No. 14, 15.07.2001, p. 5110-5120.

Research output: Contribution to journalArticle

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