Early ionic and membrane potential changes caused by the pesticide rotenone in striatal cholinergic interneurons

P. Bonsi, P. Calabresi, C. De Persis, M. Papa, D. Centonze, G. Bernardi, A. Pisani

Research output: Contribution to journalArticle

Abstract

Mitochondrial metabolism impairment has been implicated in the pathogenesis of several neurodegenerative disorders. In the present work, we combined electrophysiological recordings and microfluorometric measurements from cholinergic interneurons obtained from a rat neostriatal slice preparation. Acute application of the mitochondrial complex I inhibitor rotenone produced an early membrane hyperpolarization coupled to a fall in input resistance, followed by a late depolarizing response. Current-voltage relationship showed a reversal potential of -80 ± 3 mV, suggesting the involvement of a potassium (K+) current. Simultaneous measurement of intracellular sodium [Na+]i or calcium [Ca2+]i concentrations revealed a striking correlation between [Na+] i elevation and the early membrane hyperpolarization, whereas a significant [Ca2+]i rise matched the depolarizing phase. Interestingly, ion and membrane potential changes were mimicked by ouabain, inhibitor of the Na+-K+ATPase, and were insensitive to tetrodotoxin (TTX) or to a combination of glutamate receptor antagonists. The rotenone effects were partially reduced by blockers of ATP-sensitive K + channels, glibenclamide and tolbutamide, and largely attenuated by a low Na+-containing solution. Morphological analysis of the rotenone effects on striatal slices showed a significant decrease in the number of choline acetyltransferase (ChAT) immunoreactive cells. These results suggest that rotenone rapidly disrupts the ATP content, leading to a decreased Na +-K+ATPase function and, therefore, to [Na +]i overload. In turn, the hyperpolarizing response might be generated both by the opening of ATP-sensitive K+ channels and by Na+-activated K+ conductances. The increase in [Ca 2+]i occurs lately and does not seem to influence the early events.

Original languageEnglish
Pages (from-to)169-181
Number of pages13
JournalExperimental Neurology
Volume185
Issue number1
DOIs
Publication statusPublished - Jan 2004

Keywords

  • Calcium
  • Mitochondria
  • Progressive supranuclear palsy
  • Rotenone
  • Sodium
  • Striatum

ASJC Scopus subject areas

  • Neurology
  • Neuroscience(all)

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