title: Failure of neuronal ion exchange, not potentiated excitation, causes excitotoxicity after inhibition of oxidative phosphorylation.
abstract: Neuronal cell death during impaired energy metabolism is often attributed to increased activity at glutamate receptors, but this increase has not been directly demonstrated. We recorded responses to glutamate and N-methyl-D-aspartate in hippocampal slice CA1 neurons and glia while inhibiting mitochondrial complex II with 3-nitropropionic acid. As the period of inhibition increased, neuronal depolarization following bath application of glutamate (5 mM) or N-methyl-D-aspartate (50 microM) increased dramatically. However, depolarization upon iontophoresis of glutamate and N-methyl-D-aspartate decreased with time. A transient hyperpolarization, reflecting electrogenic sodium pump activity, was present immediately after responses to iontophoretic glutamate agonists. In the presence of the inhibitor, this hyperpolarization decreased and eventually disappeared. Even the repolarization seen upon washing of the iontophoretic or bath application of glutamate or N-methyl-D-aspartate was incomplete. Glial depolarization upon bath application of glutamate increased during inhibition, while glial depolarization upon application of N-methyl-D-aspartate decreased. Application of the N-methyl-D-aspartate antagonists aminophosphonovaleric acid (100 microM) or MK-801 (20 microM) resulted in a delay of further depolarization when applied early during the terminal decay of membrane potential following metabolic inhibition. We conclude that during impaired oxidative phosphorylation the failure of repolarizing mechanisms, not potentiated neuronal depolarization by excitants, is the primary cause of the terminal depolarization. Large glial depolarization increases the demand for neuronal ion exchange which cannot be met in situations of reduced energy metabolism. Our results provide further evidence that acute and chronic blockade of energy metabolism have different effects.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Wadsworth Center for Laboratories and Research, Albany, New York, NY 12201-0509, USA.
authors.forename: M W
authors.initials: MW
authors.lastname: Riepe
authors.forename: N
authors.initials: N
authors.lastname: Hori
authors.forename: A C
authors.initials: AC
authors.lastname: Ludolph
authors.forename: D O
authors.initials: DO
authors.lastname: Carpenter
mesh_terms: D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D018698:Glutamic Acid / Q000494:pharmacology; D007474:Ion Exchange; D007478:Iontophoresis; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D017966:Pyramidal Cells / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
chemical_list: D018698:Glutamic Acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate