Suppression of the intrinsic apoptosis pathway by synaptic activity.
Synaptic activity promotes resistance to diverse apoptotic insults, the mechanism behind which is incompletely understood. We show here that a coordinated downregulation of core components of the intrinsic apoptosis pathway by neuronal activity forms a key part of the underlying mechanism. Activity-dependent protection against apoptotic insults is associated with inhibition of cytochrome c release in most but not all neurons, indicative of anti-apoptotic signaling both upstream and downstream of this step. We find that enhanced firing activity suppresses expression of the proapoptotic BH3-only member gene Puma in a NMDA receptor-dependent, p53-independent manner. Puma expression is sufficient to induce cytochrome c loss and neuronal apoptosis. Puma deficiency protects neurons against apoptosis and also occludes the protective effect of synaptic activity, while blockade of physiological NMDA receptor activity in the developing mouse brain induces neuronal apoptosis that is preceded by upregulation of Puma. However, enhanced activity can also confer resistance to Puma-induced apoptosis, acting downstream of cytochrome c release. This mechanism is mediated by transcriptional suppression of apoptosome components Apaf-1 and procaspase-9, and limiting caspase-9 activity, since overexpression of procaspase-9 accelerates the rate of apoptosis in active neurons back to control levels. Synaptic activity does not exert further significant anti-apoptotic effects downstream of caspase-9 activation, since an inducible form of caspase-9 overrides the protective effect of synaptic activity, despite activity-induced transcriptional suppression of caspase-3. Thus, suppression of apoptotic gene expression may synergize with other activity-dependent events such as enhancement of antioxidant defenses to promote neuronal survival.
Léveillé
Frédéric
F
Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, UK.
Papadia
Sofia
S
Fricker
Michael
M
Bell
Karen F S
KF
Soriano
Francesc X
FX
Martel
Marc-André
MA
Puddifoot
Clare
C
Habel
Marlen
M
Wyllie
David J
DJ
Ikonomidou
Chrysanthy
C
Tolkovsky
Aviva M
AM
Hardingham
Giles E
GE
D015761:4-Aminopyridine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000378:metabolism; D053477:Apoptotic Protease-Activating Factor 1 / Q000378:metabolism; D001640:Bicuculline / Q000494:pharmacology; D053453:Caspase 9 / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D045304:Cytochromes c / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D026902:Potassium Channel Blockers; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D019311:Staurosporine / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D016559:Tacrolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection / Q000379:methods; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
C463061:AP20187; D051017:Apoptosis Regulatory Proteins; D053477:Apoptotic Protease-Activating Factor 1; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D018756:GABA Antagonists; D018696:Neuroprotective Agents; C488588:PUMA protein, mouse; D026902:Potassium Channel Blockers; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D049452:Green Fluorescent Proteins; D016291:Dizocilpine Maleate; D045304:Cytochromes c; D015761:4-Aminopyridine; D053453:Caspase 9; D019311:Staurosporine; D016559:Tacrolimus; D001640:Bicuculline