PT  - JOURNAL ARTICLE
AU  - Sheng-Jia Zhang
AU  - Bettina Buchthal
AU  - David Lau
AU  - Stefanie Hayer
AU  - Oliver Dick
AU  - Markus Schwaninger
AU  - Roland Veltkamp
AU  - Ming Zou
AU  - Ursula Weiss
AU  - Hilmar Bading
TI  - 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
AID  - 10.1523/JNEUROSCI.2672-10.2011
DP  - 2011 Mar 30
TA  - The Journal of Neuroscience
PG  - 4978--4990
VI  - 31
IP  - 13
4099  - http://www.jneurosci.org/content/31/13/4978.short
4100  - http://www.jneurosci.org/content/31/13/4978.full
SO  - J. Neurosci.2011 Mar 30; 31
AB  - 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.