A Signaling Cascade of Nuclear Calcium-CREB-ATF3 Activated by Synaptic NMDA That Protects against Extrasynaptic NMDA Receptor Neuronal Cell Death

This is quite a handful. Followed a calcium tracing book to here.
http://www.jneurosci.org/content/31/13/4978.full

A Signaling Cascade of Nuclear Calcium-CREB-ATF3 Activated by Synaptic NMDA Receptors Defines a Gene Repression Module That Protects against Extrasynaptic NMDA Receptor-Induced Neuronal Cell Death and Ischemic Brain Damage

Abstract

Synapse-to-nucleus signaling triggered by synaptic NMDA receptors can lead to the buildup of a neuroprotective shield. Nuclear calcium activating the cAMP response element binding protein (CREB) plays a key role in neuroprotection acquired by synaptic activity. Here we show that in mouse hippocampal neurons, the transcription factor Atf3 (activating transcription factor 3) is a direct target of CREB. Induction of ATF3 expression by CREB in hippocampal neurons was initiated by calcium entry through synaptic NMDA receptors and required nuclear calcium transients and calcium/calmodulin-dependent protein kinase IV activity. Acting as a transcriptional repressor, ATF3 protects cultured hippocampal neurons from apoptosis and extrasynaptic NMDA receptor-induced cell death triggered by bath application of NMDA or oxygen–glucose deprivation. Expression of ATF3 in vivo using stereotaxic delivery of recombinant adeno-associated virus reduces brain damage following a cerebral ischemic insult in mice. Conversion of ATF3 to a transcriptional activator transforms ATF3 into a potent prodeath protein that kills neurons in cell culture and, when expressed in vivo in the hippocampus, ablates the neuronal cell layer. These results link nuclear calcium-CREB signaling to an ATF3-mediated neuroprotective gene repression program, indicating that activity-dependent shutoff of genes is an important process for survival. ATF3 supplementation may counteract age- and disease-related neuronal cell loss caused by a reduction in synaptic activity, malfunctioning of calcium signaling toward and within the nucleus (“nuclear calciopathy”), or increases in death signaling by extrasynaptic NMDA receptors.

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Introduction

The well-being of neurons in the mammalian CNS is dependent on the balance of the activities of the survival-promoting synaptic NMDA receptor and the extrasynaptic NMDA receptor that induces cell death pathways (Hardingham et al., 2002; Hardingham and Bading, 2010). Important for the acquisition of a long-lasting neuroprotective shield following calcium entry through synaptic NMDA receptors is the propagation of calcium signals into the nucleus, the subsequent formation of a nuclear calcium/calmodulin complex, and the initiation of a genomic response (Bading, 2000, Hardingham et al., 2001; 2002; Lee et al., 2005; Papadia et al., 2005; Zhang et al., 2007; 2009; Bengtson et al., 2010). Nuclear calcium is one of the most potent activators of neuronal gene expression and controls a large gene pool that includes a gene program for acquired neuroprotection (Zhang et al., 2009). The transcription factor cAMP response element binding protein (CREB), a key target of nuclear calcium signaling (Hardingham et al., 1997; 2001; Chawla et al., 1998; Zhang et al., 2009), plays an important role in neuronal survival (Mantamadiotis et al., 2002). However, CREB is a multifunctional transcriptional regulator (Mayr and Montminy, 2001; Carlezon et al., 2005) that is also involved in a number of other processes including neuronal plasticity, addiction, neurogenesis, learning, and memory (Carlezon et al., 1998; Silva et al., 1998; Lonze and Ginty, 2002; Zhu et al., 2004; Giachino et al., 2005). CREB signaling may control multiple processes through the activation of target genes, which themselves may encode transcription factors and regulate function-specific genomic subroutines. The concept of a hierarchical transcription factor cascade that starts with a master regulator and branches off to other DNA binding proteins that serve a specific function is not new and has been implemented to control biological processes such as the specification of the body plan and pattern formation in embryonic development (Anderson, 1999; Pearson et al., 2005; Peel et al., 2005; Dequéant and Pourquié, 2008). In this study, we show that the transcriptional repressor ATF3 acts downstream of CREB to mediate the survival function. ATF3 is a direct CREB target that can protect neurons both in vitro and in vivo from death induced by stimulation of extrasynaptic NMDA receptors. CREB-ATF3 signaling, which is controlled by synaptic NMDA receptors and nuclear calcium, represents the core of an activity-regulated survival module that involves the sequential activation of transcriptional induction and gene repression.