title: Knockout of Zn transporters Zip-1 and Zip-3 attenuates seizure-induced CA1 neurodegeneration.
abstract: CA1 pyramidal neurons are the final integrators of information flow leaving the hippocampus, yet are singularly vulnerable to activity-dependent cell death. Zinc (Zn) entry into cells may add to this vulnerability. Here, we find that Slc39a1 and Slc39a3, members of the Zip (Zrt/Irt-like protein) plasmalemmal Zn transporter family, are predominantly expressed in the hippocampus. We examined Zip-1,3-deficient mice to investigate their role in neurodegeneration following intense synaptic activation. When isolated by blockade of NMDA receptors and voltage-gated calcium channels, the absence of both transporters slowed passive Zn uptake into CA1 neurons measured with intracellular fluorescent Zn dyes. In vivo CA1 cell damage following kainic acid exposure was greatly attenuated. Consistent with the hypothesis that Zn entry contributes to neurodegeneration, Znt-3-deficient mice lacking synaptic Zn also show less hippocampal cell damage following kainic acid injection. Zip transporters may provide selective therapeutic targets to protect these neurons from early Zn-induced neurodegeneration following injury.
authors.affiliation: Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Qian
authors.forename: Kaiping
authors.initials: K
authors.lastname: Xu
authors.forename: Jong
authors.initials: J
authors.lastname: Yoo
authors.forename: Tim T
authors.initials: TT
authors.lastname: Chen
authors.forename: Glen
authors.initials: G
authors.lastname: Andrews
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Noebels
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000503:physiopathology*; D027682:Cation Transport Proteins / Q000172:deficiency*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D004569:Electroencephalography / Q000379:methods; D018690:Excitatory Amino Acid Agonists / Q000009:adverse effects; D005452:Fluoresceins; D015967:Gene Expression Regulation, Viral / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D007608:Kainic Acid / Q000009:adverse effects; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000209:etiology* / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009930:Organic Chemicals; D018408:Patch-Clamp Techniques / Q000379:methods; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000473:pathology*; D014741:Video Recording / Q000379:methods; D015032:Zinc / Q000378:metabolism
chemical_list: D027682:Cation Transport Proteins; D018690:Excitatory Amino Acid Agonists; D005452:Fluoresceins; C409466:NR1 NMDA receptor; D009930:Organic Chemicals; D016194:Receptors, N-Methyl-D-Aspartate; C485744:Slc39a1 protein, mouse; C498426:Slc39a3 protein, mouse; C485184:enhanced green fluorescent protein; C435731:fluoro jade; D049452:Green Fluorescent Proteins; D015032:Zinc; D007608:Kainic Acid