Neuronal vulnerability following inhibition of mitochondrial complex II: A possible ionic mechanism for Huntington's disease

Emilia Saulle, Paolo Gubellini, Barbara Picconi, Diego Centonze, Domenicantonio Tropepi, Antonio Pisani, Michele Morari, Matteo Marti, Luisa Rossi, Michele Papa, Giorgio Bernardi, Paolo Calabresi

Research output: Contribution to journalArticlepeer-review

Abstract

An impaired complex II (succinate dehydrogenase, SD) striatal mitochondrial activity is one of the prominent metabolic alterations in Huntington's disease (HD), and intoxication with 3-nitropropionic acid (3-NP), an inhibitor of mitochondrial complex II, mimics the motor abnormalities and the pathology of HD. We found that striatal spiny neurons responded to this toxin with an irreversible membrane depolarization/inward current, while cholinergic interneurons showed a hyperpolarization/outward current. Both these currents were sensitive to intracellular concentration of ATP. The 3-NP-induced depolarization was associated with an increased release of endogenous GABA, while acetylcholine levels were reduced. Moreover, 3-NP induced a higher depolarization in presymptomatic R6/2 HD transgenic mice compared to wild-type (WT) mice, showing an increased susceptibility to SD inhibition. Conversely, the hyperpolarization did not significantly differ from the one recorded in WT mice. The diverse membrane changes induced by SD inhibition may contribute to the cell-type-specific neuronal death in HD.

Original languageEnglish
Pages (from-to)9-20
Number of pages12
JournalMolecular and Cellular Neuroscience
Volume25
Issue number1
DOIs
Publication statusPublished - Jan 2004

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience
  • Developmental Neuroscience

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