Nuclear Ca2+ and the cAMP response element-binding protein family mediate a late phase of activity-dependent neuroprotection.
The mechanism by which physiological synaptic NMDA receptor activity promotes neuronal survival is not well understood. Here, we show that that an episode of synaptic activity can promote neuroprotection for a long time after that activity has ceased. This long-lasting or "late phase" of neuroprotection is dependent on nuclear calcium signaling and cAMP response element (CRE)-mediated gene expression. In contrast, neuroprotection evoked acutely by ongoing synaptic activity relies solely on the activation of the phosphatidylinositol 3-kinase/Akt pathway. This "acute phase" does not require nuclear calcium signaling and is independent of activation of the CRE-binding protein (CREB) family of transcription factors. Thus, activity-dependent neuroprotection comprises two mechanistically distinct phases that differ in their spatial requirements for calcium and in their reliance on the CREB family.
Papadia
Sofia
S
Centre for Neuroscience Research, University of Edinburgh, Summerhall, Edinburgh EH9 1QH, United Kingdom.
Stevenson
Patrick
P
Hardingham
Neil R
NR
Bading
Hilmar
H
Hardingham
Giles E
GE
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001640:Bicuculline / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D002518:Ceramides / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018755:GABA Agonists; D018756:GABA Antagonists / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000096:biosynthesis; D006624:Hippocampus; D066298:In Vitro Techniques; D009118:Muscimol / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection / Q000379:methods; D014212:Tretinoin / Q000494:pharmacology
D002518:Ceramides; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists; D018756:GABA Antagonists; D018696:Neuroprotective Agents; D026941:Sodium Channel Blockers; D049452:Green Fluorescent Proteins; D009118:Muscimol; D013779:Tetrodotoxin; D014212:Tretinoin; D016291:Dizocilpine Maleate; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D002118:Calcium; D001640:Bicuculline