title: Zinc induces long-term upregulation of T-type calcium current in hippocampal neurons in vivo.
abstract: Extracellular zinc can induce numerous acute and persistent physiological and toxic effects in neurons by acting at their plasma membrane or intracellularly following permeation or uptake into them. Zinc acutely and reversibly blocks T-type voltage-gated calcium current (I(CaT)), but the long-term effect of zinc on this current has not been studied. Because chemically induced status epilepticus (SE) results in the release of zinc into the extracellular space, as well as in a long-lasting increase in I(CaT) in CA1 pyramidal cells, we hypothesized that zinc may play a causative role in I(CaT) upregulation. We tested this hypothesis by monitoring for 18 days the effects of zinc and ibotenic acid (a neurotoxic agent serving as control for zinc), injected into the right lateral ventricle, on I(CaT) in rat CA1 pyramidal cells. Both zinc and ibotenic acid caused marked hippocampal lesions on the side of injection, but only minor damage to contralateral hippocampi. Zinc, but not ibotenic acid, caused upregulation of a nickel-sensitive I(CaT) in a subset of contralateral CA1 pyramidal cells, appearing 2 days after injection and lasting for about 2 weeks thereafter. In contrast, acute application of zinc to CA1 pyramidal cells promptly blocked I(CaT). These data indicate that extracellular zinc has a dual effect on I(CaT), blocking it acutely while causing its long-term upregulation. Through the latter effect, zinc may regulate the intrinsic excitability of principal neurons, particularly in pathological conditions associated with enhanced release of zinc, such as SE.
authors.affiliation: Department of Medical Neurobiology, IMRIC, Hebrew University-Hadassah School of Medicine, Jerusalem 91120, Israel. dekstein@hadassah.org.il
authors.forename: Dana
authors.initials: D
authors.lastname: Ekstein
authors.forename: Felix
authors.initials: F
authors.lastname: Benninger
authors.forename: Moshe
authors.initials: M
authors.lastname: Daninos
authors.forename: Julika
authors.initials: J
authors.lastname: Pitsch
authors.forename: Karen M J
authors.initials: KM
authors.lastname: van Loo
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Becker
authors.forename: Yoel
authors.initials: Y
authors.lastname: Yaari
mesh_terms: D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D020747:Calcium Channels, T-Type / Q000187:drug effects* / Q000502:physiology; D016923:Cell Death; D006624:Hippocampus / Q000502:physiology*; D007051:Ibotenic Acid / Q000494:pharmacology; D008297:Male; D009532:Nickel / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D015032:Zinc / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D020747:Calcium Channels, T-Type; D007051:Ibotenic Acid; D009532:Nickel; D015032:Zinc