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 adenoassociated 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.

Inversion of Sonic hedgehog action on its canonical pathway by electrical activity

“…Although CREB is mostly known as an activator, it has been found to inhibit transcription, and whether it acts as a repressor depends on its phosphorylation status (41), the partners recruited in transcriptional complexes (42), and the regulatory region of the gene to which CREB binds (43). Alternatively, CREB negative effect on gli1 transcription may be indirect by inducing expression of a repressor (44).…”

The Stress-Induced Atf3-Gelsolin Cascade Underlies Dendritic Spine Deficits in Neuronal Models of Tuberous Sclerosis Complex

“…In wild-type neurons, overexcitability due to excessive NMDA-receptor signaling activates the calcium-CREB pathway to eventually enhance the expression of Atf3 (Hashimoto et al, 2002;Zhang et al, 2009Zhang et al, , 2011. Atf3 expression is also induced in sensory and motor neuron following axotomy (Tsujino et al, 2000;Seijffers et al, 2007).…”

“…Our previous study has demonstrated an mTOR-dependent induction of Hmox1 (heme oxygenase-1) in Tsc2-deficient neurons, indicating an enhanced oxidative stress response (Di Nardo et al, 2009). Atf3 is a transcription factor in the CREB protein family that is induced by action potential bursting and nuclear calcium signaling Zhang et al, 2011;Hunt et al, 2012). Hmox1 also has anti-inflammatory effects.…”

ATF3 expression improves motor function in the ALS mouse model by promoting motor neuron survival and retaining muscle innervation

“…ATF3 transcriptional targets vary in different cell types and conditions, resulting in diverse influences on cellular phenomena, such as cell survival, proliferation, and death (15,16). In neurons (17), induction of ATF3 expression prevents cell death and promotes neurite formation and elongation, leading to enhanced nerve regeneration through transcriptional induction of survival and growth-associated genes (18)(19)(20)(21)(22)(23)(24)(25)(26). Intact adult motor neurons do not normally express ATF3.…”