PT  - JOURNAL ARTICLE
AU  - Frédéric Léveillé
AU  - Sofia Papadia
AU  - Michael Fricker
AU  - Karen F. S. Bell
AU  - Francesc X. Soriano
AU  - Marc-André Martel
AU  - Clare Puddifoot
AU  - Marlen Habel
AU  - David J. Wyllie
AU  - Chrysanthy Ikonomidou
AU  - Aviva M. Tolkovsky
AU  - Giles E. Hardingham
TI  - Suppression of the Intrinsic Apoptosis Pathway by Synaptic Activity
AID  - 10.1523/JNEUROSCI.5115-09.2010
DP  - 2010 Feb 17
TA  - The Journal of Neuroscience
PG  - 2623--2635
VI  - 30
IP  - 7
4099  - http://www.jneurosci.org/content/30/7/2623.short
4100  - http://www.jneurosci.org/content/30/7/2623.full
SO  - J. Neurosci.2010 Feb 17; 30
AB  - 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.