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The Journal of Neuroscience, October 26, 2005, 25(43):10029-10040; doi:10.1523/JNEUROSCI.2652-05.2005

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Cellular/Molecular
Partial Mitochondrial Inhibition Causes Striatal Dopamine Release Suppression and Medium Spiny Neuron Depolarization via H₂O₂ Elevation, Not ATP Depletion

Li Bao, Marat V. Avshalumov, and Margaret E. Rice

Department of Physiology and Neuroscience and Department of Neurosurgery, New York University School of Medicine, New York, New York 10016

Mitochondrial dysfunction is a potential causal factor in Parkinson's disease. We show here that acute exposure to the mitochondrial complex I inhibitor rotenone (30-100 nM; 30 min) causes concentration-dependent suppression of single-pulse evoked dopamine (DA) release monitored in real time with carbon-fiber microelectrodes in guinea pig striatal slices, with no effect on DA content. Suppression of DA release was prevented by the sulfonylurea glibenclamide, implicating ATP-sensitive K⁺ (K_ATP) channels; however, tissue ATP was unaltered. Because K_ATP channels can be activated by hydrogen peroxide (H₂O₂), as well as by low ATP, we examined the involvement of rotenone-enhanced H₂O₂ generation. Confirming an essential role for H₂O₂, the inhibition of DA release by rotenone was prevented by catalase, a peroxide-scavenging enzyme. Striatal H₂O₂ generation during rotenone exposure was examined in individual medium spiny neurons using fluorescence imaging with dichlorofluorescein (DCF). An increase in intracellular H₂O₂ levels followed a similar time course to that of DA release suppression and was accompanied by cell membrane depolarization, decreased input resistance, and increased excitability. Extracellular catalase markedly attenuated the increase in DCF fluorescence and prevented rotenone-induced effects on membrane properties; membrane changes were also largely prevented by flufenamic acid, a blocker of transient receptor potential (TRP) channels. Thus, partial mitochondrial inhibition can cause functional DA denervation via H₂O₂ and K_ATP channels, without DA or ATP depletion. Furthermore, amplified H₂O₂ levels and TRP channel activation in striatal spiny neurons indicate potential sources of damage in these cells. Overall, these novel factors could contribute to parkinsonian motor deficits and neuronal degeneration caused by mitochondrial dysfunction.

Key words: basal ganglia; K_ATP channels; medium spiny neurons; mitochondria; Parkinson's disease; pesticide; rotenone

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Received June 28, 2005; revised September 12, 2005; accepted September 20, 2005.

This article has been cited by other articles:

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