Blockade of Ca2+-Permeable AMPA/Kainate Channels Decreases Oxygen–Glucose Deprivation-Induced Zn2+Accumulation and Neuronal Loss in Hippocampal Pyramidal Neurons
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Synaptic release of Zn2+ and its translocation into postsynaptic neurons probably contribute to neuronal injury after ischemia or epilepsy. Studies in cultured neurons have revealed that of the three major routes of divalent cation entry, NMDA channels, voltage-sensitive Ca2+ channels (VSCCs), and Ca2+-permeable AMPA/kainate (Ca-A/K) channels, Ca-A/K channels exhibit the highest permeability to exogenously applied Zn2+. However, routes through which synaptically released Zn2+ gains entry to postsynaptic neurons have not been characterized in vivo. To model ischemia-induced Zn2+ movement in a system approximating the in vivo situation, we subjected mouse hippocampal slice preparations to controlled periods of oxygen and glucose deprivation (OGD). Timm's staining revealed little reactive Zn2+ in CA1 and CA3 pyramidal neurons of slices exposed in the presence of O2 and glucose. However, 15 min of OGD resulted in marked labeling in both regions. Whereas strong Zn2+ labeling persisted if both the NMDA antagonist MK-801 and the VSCC blocker Gd3+ were present during OGD, the presence of either the Ca-A/K channel blocker 1-naphthyl acetyl spermine (NAS) or the extracellular Zn2+ chelator Ca2+ EDTA substantially decreased Zn2+ accumulation in pyramidal neurons of both subregions. In parallel experiments, slices were subjected to 5 min OGD exposures as described above, followed 4 hr later by staining with the cell-death marker propidium iodide. As in the Timm's staining experiments, substantial CA1 or CA3 pyramidal neuronal damage occurred despite the presence of MK-801 and Gd3+, whereas injury was decreased by NAS or by Ca2+ EDTA (in CA1).
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Calcium-permeable AMPA receptors are a major entry point for zinc.
“Ca 2+ -permeable AMPA receptors are a major entry point of zinc [111-113].”
From Parvalbumin interneuron vulnerability and brain disorders (2021) · cites this paper as [111]
Blocking calcium-permeable AMPA receptors reduces cortical neuron death in an in vitro traumatic brain injury model, hippocampal pyramidal neuron loss in an oxygen-glucose deprivation slice model, and retinal ganglion cell loss in a glaucoma rat model.
“Consistent with the notion that the presence of Ca 2+ -permeable AMPA receptors contributes to the vulnerability of PV-INs, blocking of these receptors attenuates cortical neuron death in an in vitro model of traumatic brain injury; attenuates hippocampal pyramidal neuron loss in a mouse hippocampal slice model of oxygen-glucose deprivation; and attenuates retinal ganglion cells loss in a rat”
From Parvalbumin interneuron vulnerability and brain disorders (2021) · cites this paper as [111]
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Self-citation
- Authors
- Yin, H. Z., Sensi, S. L., Ogoshi, F., & Weiss, J. H.
- Affiliations
- University of Chieti-Pescara (IT)
- University of California, Irvine (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2002-02-15
- Volume
- 22
- Issue
- 4
- Pages
- 1273-1279
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6757569
- OpenAlex
- W2149684302
- Cited by
- 143
- References
- 43
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 1 · 2022: 4 · 2021: 2 · 2020: 2 · 2019: 5 · 2018: 5 · 2017: 2 · 2016: 4 · 2015: 6 · 2014: 5 · 2013: 5 · 2012: 7
- FWCI
- 3.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association
- National Institutes of Health (5k02ag000836-05, 5r01ns030884-11, NS30884)
- National Institute on Aging (AG00836, AG 00919, K01AG000919)
- National Institute of Neurological Disorders and Stroke (T32NS007444, NS 30884, 5T32NS07444)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Keywords
- zinc accumulation, oxygen-glucose deprivation, hippocampal pyramidal neurons, neuronal cell death, ischemia, zinc chelation, NMDA receptor antagonism, voltage-gated calcium channels, CA1 and CA3
- MeSH terms
- Animals, Calcium, Calcium Channel Blockers, Cells, Cultured, Hypoxia, Brain, Cobalt, Dose-Response Relationship, Drug, Glucose, Hippocampus, Spermine, Zinc, Cell Hypoxia, Pyramidal Cells, Receptors, AMPA, Receptors, Kainic Acid, Kainic Acid Receptors, Excitatory Amino Acid Antagonists, Coculture Techniques, Mice
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