RT Journal Article
SR Electronic
T1 Suppression of the Intrinsic Apoptosis Pathway by Synaptic Activity
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 2623
OP 2635
DO 10.1523/JNEUROSCI.5115-09.2010
VO 30
IS 7
A1 Frédéric Léveillé
A1 Sofia Papadia
A1 Michael Fricker
A1 Karen F. S. Bell
A1 Francesc X. Soriano
A1 Marc-André Martel
A1 Clare Puddifoot
A1 Marlen Habel
A1 David J. Wyllie
A1 Chrysanthy Ikonomidou
A1 Aviva M. Tolkovsky
A1 Giles E. Hardingham
YR 2010
UL http://www.jneurosci.org/content/30/7/2623.abstract
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.