Suppression of the Intrinsic Apoptosis Pathway by Synaptic Activity

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 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.

Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy

“…To determine whether the observed cell death was due to increased apoptosis, the effect of pan-caspase inhibitor QVD-oph was measured (30). Treatment with the pan-caspase inhibitor decreased the cumulative HR of M337V and CTRL astrocytes.…”

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

“…Not all NMDAR contribute to neuronal cell death in excitotoxicity, since the synaptic and extrasynaptic receptor populations are differentially coupled to the activation of intracellular signaling mechanisms: the latter receptors mediate the influx of calcium ions leading to mitochondrial injury (Stanika et al, 2009), activation of pro-apoptotic genes (Leveille et al, 2010), cleavage of fodrin and the sodium-calcium exchanger type-3 (NCX3) by calpains (Xu et al, 2009a), and cell death (Hardingham et al, 2002). On the other hand, activation of synaptic NMDAR is not coupled to hippocampal neuron damage (Hardingham et al, 2002), but rather promotes resistance to oxidative insults and prevents accumulation of reactive oxygen species in cortical neurons (Papadia et al, 2008) (Fig.…”

“…1). Furthermore, synaptic NMDA receptors induce genomic alterations that render neurons more resistant to apoptosis and oxidative insults (Hardingham et al, 2002;Leveille et al, 2010;Kaufman et al, 2012;Karpova et al, 2013). However, the relative role of synaptic and extrasynaptic NMDAR in excitotoxic cell death needs further investigation, considering the conflicting results showing neurotoxicity induced by synaptic NMDAR (Papouin et al, 2012) and the evidence pointing to a role for these receptors in hypoxic excitotoxic death (Wroge et al, 2012).…”

“…The [Ca 2+ ] i overload increases calpain activity with consequent cleavage of several proteins, which contributes to cell death (Araujo et al, 2004;Sanchez-Gomez et al, 2011). Calcium influx through synaptic NMDAR induces signaling pathways which upregulate the transcription of anti-apoptotic genes and genes involved in antioxidant defenses (Hardingham et al, 2002;Leveille et al, 2010;Kaufman et al, 2012;Karpova et al, 2013). In contrast, the excessive activation of extrasynaptic NMDAR induces signaling pathways promoting transcription of pro-apoptotic genes and mitochondrial injury, contributing to excitotoxic cell death (Stanika et al, 2009;Leveille et al, 2010;Kaufman et al, 2012;Wroge et al, 2012).…”

“…Calcium influx through synaptic NMDAR induces signaling pathways which upregulate the transcription of anti-apoptotic genes and genes involved in antioxidant defenses (Hardingham et al, 2002;Leveille et al, 2010;Kaufman et al, 2012;Karpova et al, 2013). In contrast, the excessive activation of extrasynaptic NMDAR induces signaling pathways promoting transcription of pro-apoptotic genes and mitochondrial injury, contributing to excitotoxic cell death (Stanika et al, 2009;Leveille et al, 2010;Kaufman et al, 2012;Wroge et al, 2012). Moreover, extrasynaptic NMDAR activity induces calpainmediated cleavage of Myocyte enhancer factor 2 (MEF2), glutamic acid decarboxylase (GAD65/67), Fodrin, NCX3, and STEP (Xu et al, 2009a,b;Monnerie et al, 2010;Wei et al, 2012).…”