Get access

Differential responsiveness of rat striatal nerve endings to the mitochondrial toxin 3-nitropropionic acid: implications for Huntington's disease

Authors

  • Matteo Marti,

    1. Department of Experimental and Clinical Medicine, Section of Pharmacology, via Fossato di Mortara 17–19, 44100 Ferrara, Italy
    2. Neuroscience Centre and
    Search for more papers by this author
  • Flora Mela,

    1. Department of Experimental and Clinical Medicine, Section of Pharmacology, via Fossato di Mortara 17–19, 44100 Ferrara, Italy
    2. Neuroscience Centre and
    Search for more papers by this author
  • Linda Ulazzi,

    1. Department of Experimental and Clinical Medicine, Section of Pharmacology, via Fossato di Mortara 17–19, 44100 Ferrara, Italy
    2. Neuroscience Centre and
    Search for more papers by this author
  • Stefania Hanau,

    1. Department of Biochemistry and Molecular Biology, University of Ferrara, via Fossato di Mortara 17–19, 44100 Ferrara, Italy
    Search for more papers by this author
  • Sara Stocchi,

    1. Department of Experimental and Clinical Medicine, Section of Pharmacology, via Fossato di Mortara 17–19, 44100 Ferrara, Italy
    2. Neuroscience Centre and
    Search for more papers by this author
  • Francesca Paganini,

    1. Department of Experimental and Clinical Medicine, Section of Pharmacology, via Fossato di Mortara 17–19, 44100 Ferrara, Italy
    2. Neuroscience Centre and
    Search for more papers by this author
  • Lorenzo Beani,

    1. Department of Experimental and Clinical Medicine, Section of Pharmacology, via Fossato di Mortara 17–19, 44100 Ferrara, Italy
    2. Neuroscience Centre and
    Search for more papers by this author
  • Clementina Bianchi,

    1. Department of Experimental and Clinical Medicine, Section of Pharmacology, via Fossato di Mortara 17–19, 44100 Ferrara, Italy
    2. Neuroscience Centre and
    Search for more papers by this author
  • Michele Morari

    1. Department of Experimental and Clinical Medicine, Section of Pharmacology, via Fossato di Mortara 17–19, 44100 Ferrara, Italy
    2. Neuroscience Centre and
    Search for more papers by this author

: Dr Michele Morari, as above.
E-mail: m.morari@unife.it

Abstract

Rat striatal synaptosomes and slices were used to investigate the responsiveness of different populations of nerve terminals to 3-nitropropionic acid (3-NP), a suicide inhibitor of the mitochondrial enzyme succinate dehydrogenase, and to elucidate the ionic mechanisms involved. 3-NP (0.3–3 mm) stimulated spontaneous γ-aminobutyric acid (GABA), glutamate and [3H]-dopamine efflux but left unchanged acetylcholine efflux from synaptosomes. This effect was associated with a >70% inhibition of succinate dehydrogenase, as measured in the whole synaptosomal population. The facilitation was not dependent on extracellular Ca2+ but relied on voltage-dependent Na+ channel opening, because it was prevented by tetrodotoxin and riluzole. 3-NP also elevated spontaneous glutamate efflux from slices but in a tetrodotoxin-insensitive way. To investigate whether energy depletion could change the responsiveness of nerve endings to a depolarizing stimulus, synaptosomes were pretreated with 3-NP and challenged with pulses of KCl evoking ‘quasi-physiological’ neurotransmitter release. 3-NP potentiated the K+-evoked GABA, glutamate and [3H]-dopamine release but inhibited the K+-evoked acetylcholine release. The 3-NP induced potentiation of GABA release was Ca2+-dependent and prevented by tetrodotoxin and riluzole whereas the 3-NP-induced inhibition of acetylcholine release was tetrodotoxin- and riluzole-insensitive but reversed by glipizide, an ATP-dependent K+ channel inhibitor. We conclude that the responsiveness of striatal nerve endings to 3-NP relies on activation of different ionic conductances, and suggest that the selective survival of striatal cholinergic interneurons following chronic 3-NP treatment (as in models of Huntington's disease) may rely on the opening of ATP-dependent K+ channels, which counteracts the fall in membrane potential as a result of mitochondrial impairment.

Ancillary