Abstract
Synaptic activity increases the resistance of neurons to diverse apoptotic insults; however, the underlying mechanisms remain less well understood. Zinc promotes cell survival under varied conditions, but the role of synaptically released zinc in the activity-dependent anti-apoptotic effect is unknown. Using cultured hippocampal slices and primary neurons we show that a typical apoptosis inducer-staurosporine (STP) was able to cause concentration-dependent apoptotic cell death in brain slices; Enhanced synaptic activity by bicuculline (Bic)/4-Aminopyridine (AP) treatment effectively prevented neurons from STP-induced cell apoptosis, as indicated by increased cell survival and suppressed caspase-3 activity. Application of Ca-EDTA, a cell membrane-impermeable zinc chelator which can efficiently capture the synaptically released zinc, completely blocked the neuronal activity-dependent anti-apoptotic effect. Same results were also observed in cultured primary hippocampal neurons. Therefore, our results indicate that synaptic activity improves neuronal resistance to apoptosis via synaptically released zinc.
MeSH terms
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4-Aminopyridine / pharmacology
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Animals
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Apoptosis / drug effects
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Apoptosis / physiology*
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Bicuculline / pharmacology
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Caspase 3 / metabolism
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Cell Survival / drug effects
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Cell Survival / physiology
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Cells, Cultured
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Chelating Agents / pharmacology
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Dose-Response Relationship, Drug
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Hippocampus / drug effects
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Hippocampus / pathology
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Hippocampus / physiology
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Male
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Neurons / drug effects
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Neurons / pathology
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Neurons / physiology*
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Neuroprotection / drug effects
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Neuroprotection / physiology*
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Neuroprotective Agents / pharmacology
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Rats, Sprague-Dawley
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Staurosporine / toxicity
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Synaptic Transmission / drug effects
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Synaptic Transmission / physiology*
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Tissue Culture Techniques
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Zinc / metabolism*
Substances
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Chelating Agents
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Neuroprotective Agents
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4-Aminopyridine
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Casp3 protein, rat
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Caspase 3
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Staurosporine
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Zinc
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Bicuculline
Grants and funding
This work was supported by the National Natural Science Foundation of China (No: 81471304, 81271403, 91132305), Natural Science Foundation of Hubei Province, China (No: 2015CKC897), and the foundations from Hubei Health and Family Planning Commission (No: WJ2015MB152) and Integrated Innovative Team for Major Human Diseases Program of Tongji Medical College, HUST.