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
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...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
March 30, 2011
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| In: |
The journal of neuroscience
Year: 2011, Volume: 31, Issue: 13, Pages: 4978-4990 |
| ISSN: | 1529-2401 |
| DOI: | 10.1523/JNEUROSCI.2672-10.2011 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1523/JNEUROSCI.2672-10.2011 Verlag, lizenzpflichtig, Volltext: https://www.jneurosci.org/content/31/13/4978 
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| Author Notes: | Sheng-Jia Zhang, Bettina Buchthal, David Lau, Stefanie Hayer, Oliver Dick, Markus Schwaninger, Roland Veltkamp, Ming Zou, Ursula Weiss, and Hilmar Bading |
| Summary: | 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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| Item Description: | Gesehen am 16.01.2023 |
| Physical Description: | Online Resource |
| ISSN: | 1529-2401 |
| DOI: | 10.1523/JNEUROSCI.2672-10.2011 |