Suppression of the Intrinsic Apoptosis Pathway by Synaptic Activity
Open Access
- 17 February 2010
- journal article
- Published by Society for Neuroscience in Journal of Neuroscience
- Vol. 30 (7), 2623-2635
- https://doi.org/10.1523/jneurosci.5115-09.2010
Abstract
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 cytochromecrelease 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 genePumain a NMDA receptor-dependent, p53-independent manner. Puma expression is sufficient to induce cytochromecloss 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 cytochromecrelease. 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.This publication has 82 references indexed in Scilit:
- Coupling of the NMDA receptor to neuroprotective and neurodestructive eventsBiochemical Society Transactions, 2009
- The Proapoptotic BH3-Only, Bcl-2 Family Member, Puma Is Critical for Acute Ethanol-Induced Neuronal ApoptosisJournal of Neuropathology and Experimental Neurology, 2009
- Bad Targets the Permeability Transition Pore Independent of Bax or Bak to Switch between Ca2+-Dependent Cell Survival and DeathMolecular Cell, 2009
- Induction of sulfiredoxin expression and reduction of peroxiredoxin hyperoxidation by the neuroprotective Nrf2 activator 3H‐1,2‐dithiole‐3‐thioneJournal of Neurochemistry, 2008
- Synaptic NMDA receptor activity boosts intrinsic antioxidant defensesNature Neuroscience, 2008
- The BCL-2 protein family: opposing activities that mediate cell deathNature Reviews Molecular Cell Biology, 2008
- Deletion of the BH3-only protein puma protects motoneurons from ER stress-induced apoptosis and delays motoneuron loss in ALS miceProceedings of the National Academy of Sciences of the United States of America, 2007
- Chromatin modification of Apaf-1 restricts the apoptotic pathway in mature neuronsThe Journal of cell biology, 2007
- Pro-survival signalling from the NMDA receptorBiochemical Society Transactions, 2006
- Oxidative stress and neurodegeneration: where are we now?Journal of Neurochemistry, 2006