title: Early ionic and membrane potential changes caused by the pesticide rotenone in striatal cholinergic interneurons.
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 [Ca2+]i occurs lately and does not seem to influence the early events.
authors.affiliation: Clinica Neurologica, Dipartimento di Neuroscienze, Università di Roma Tor Vergata, Fondazione Santa Lucia, IRCCS, 00133 Rome, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Bonsi
authors.forename: P
authors.initials: P
authors.lastname: Calabresi
authors.forename: C
authors.initials: C
authors.lastname: De Persis
authors.forename: M
authors.initials: M
authors.lastname: Papa
authors.forename: D
authors.initials: D
authors.lastname: Centonze
authors.forename: G
authors.initials: G
authors.lastname: Bernardi
authors.forename: A
authors.initials: A
authors.lastname: Pisani
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D007395:Interneurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D017136:Ion Transport / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects* / Q000502:physiology; D018715:Microscopy, Video; D018408:Patch-Clamp Techniques; D010575:Pesticides / Q000633:toxicity*; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012402:Rotenone / Q000633:toxicity*; D012964:Sodium / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D010575:Pesticides; D026902:Potassium Channel Blockers; D026941:Sodium Channel Blockers; D012402:Rotenone; D012964:Sodium; D002795:Choline O-Acetyltransferase; D000254:Sodium-Potassium-Exchanging ATPase; D011188:Potassium; D002118:Calcium