| 14697328 |
Bonsi P, Calabresi P, De Persis C, Papa M, Centonze D, Bernardi G, Pisani A: Early ionic and membrane potential changes caused by the pesticide rotenone in striatal cholinergic interneurons. Exp Neurol. 2004 Jan;185(1):169-81.
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 [Ca2+] i occurs lately and does not seem to influence the early events. |
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