title: 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.
authors: Department of Neurobiology and Interdisciplinary Center for Neurosciences, University of Heidelberg, 69120 Heidelberg, Germany.
authors: Sheng-Jia
authors: SJ
authors: Zhang
authors: Bettina
authors: B
authors: Buchthal
authors: David
authors: D
authors: Lau
authors: Stefanie
authors: S
authors: Hayer
authors: Oliver
authors: O
authors: Dick
authors: Markus
authors: M
authors: Schwaninger
authors: Roland
authors: R
authors: Veltkamp
authors: Ming
authors: M
authors: Zou
authors: Ursula
authors: U
authors: Weiss
authors: Hilmar
authors: H
authors: Bading
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050882:CREB-Binding Protein / Q000378:metabolism / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology*; D016923:Cell Death / Q000235:genetics; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D002645:Chickens; D020868:Gene Silencing / Q000502:physiology; D008297:Male; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000502:physiology*; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology*
chemical_list: D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D016194:Receptors, N-Methyl-D-Aspartate; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse