Browse
Submit Data
Databases
API
Help

Dataset Information

14 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

NMDA-induced neuronal survival is mediated through nuclear factor I-A in mice.

ABSTRACT: Identification of the signaling pathways that mediate neuronal survival signaling could lead to new therapeutic targets for neurologic disorders and stroke. Sublethal doses of NMDA can induce robust endogenous protective mechanisms in neurons. Through differential analysis of primary library expression and microarray analyses, here we have shown that nuclear factor I, subtype A (NFI-A), a member of the NFI/CAAT-box transcription factor family, is induced in mouse neurons by NMDA receptor activation in a NOS- and ERK-dependent manner. Knockdown of NFI-A induction using siRNA substantially reduced the neuroprotective effects of sublethal doses of NMDA. Further analysis indicated that NFI-A transcriptional activity was required for the neuroprotective effects of NMDA receptor activation. Additional evidence of the neuroprotective effects of NFI-A was provided by the observations that Nfia(-/-) neurons were highly sensitive to NMDA-induced excitotoxicity and were more susceptible to developmental cell death than wild-type neurons and that Nfia(+/-) mice were more sensitive to NMDA-induced intrastriatal lesions than were wild-type animals. These results identify NFI-A as what we believe to be a novel neuroprotective transcription factor with implications in neuroprotection and neuronal plasticity following NMDA receptor activation.

SUBMITTER: Zheng S

PROVIDER: S-EPMC2898580 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Extrasynaptic NMDA receptor-induced tau overexpression mediates neuronal death through suppressing survival signaling ERK phosphorylation.

Project description:Intracellular accumulation of the hyperphosphorylated tau is a pathological hallmark in the brain of Alzheimer disease. Activation of extrasynaptic NMDA receptors (E-NMDARs) induces excitatory toxicity that is involved in Alzheimer's neurodegeneration. However, the intrinsic link between E-NMDARs and the tau-induced neuronal damage remains elusive. In the present study, we showed in cultured primary cortical neurons that activation of E-NMDA receptors but not synaptic NMDA receptors dramatically increased tau mRNA and protein levels, with a simultaneous neuronal degeneration and decreased neuronal survival. Memantine, a selective antagonist of E-NMDARs, reversed E-NMDARs-induced tau overexpression. Activation of E-NMDARs in wild-type mouse brains resulted in neuron loss in hippocampus, whereas tau deletion in neuronal cultures and in the mouse brains rescued the E-NMDARs-induced neuronal death and degeneration. The E-NMDARs-induced tau overexpression was correlated with a reduced ERK phosphorylation, whereas the increased MEK activity, decreased binding and activity of ERK phosphatase to ERK, and increased ERK phosphorylation were observed in tau knockout mice. On the contrary, addition of tau proteins promoted ERK dephosphorylation in vitro. Taking together, these results indicate that tau overexpression mediates the excitatory toxicity induced by E-NMDAR activation through inhibiting ERK phosphorylation.

| S-EPMC5260900 | biostudies-literature

Astrocyte NMDA receptors' activity sustains neuronal survival through a Cdk5-Nrf2 pathway.

Project description:Neurotransmission unavoidably increases mitochondrial reactive oxygen species. However, the intrinsic antioxidant defense of neurons is weak and hence the mechanism whereby these cells are physiologically protected against oxidative damage is unknown. Here we found that the antioxidant defense of neurons is repressed owing to the continuous protein destabilization of the master antioxidant transcriptional activator, nuclear factor-erythroid 2-related factor-2 (Nrf2). By contrast, Nrf2 is highly stable in neighbor astrocytes explaining their robust antioxidant defense and resistance against oxidative stress. We also show that subtle and persistent stimulation of N-methyl-d-aspartate receptors (NMDAR) in astrocytes, through a mechanism not requiring extracellular Ca²? influx, upregulates a signal transduction pathway involving phospholipase C-mediated endoplasmic reticulum release of Ca²? and protein kinase C? activation. Active protein kinase C? promotes, by phosphorylation, the stabilization of p35, a cyclin-dependent kinase-5 (Cdk5) cofactor. Active p35/Cdk5 complex in the cytosol phosphorylates Nrf2 at Thr(395), Ser(433) and Thr(439) that is sufficient to promote Nrf2 translocation to the nucleus and induce the expression of antioxidant genes. Furthermore, this Cdk5-Nrf2 transduction pathway boosts glutathione metabolism in astrocytes efficiently protecting closely spaced neurons against oxidative damage. Thus, intercellular communication through NMDAR couples neurotransmission with neuronal survival.

| S-EPMC4648333 | biostudies-literature

Nurr1 protein is required for N-methyl-D-aspartic acid (NMDA) receptor-mediated neuronal survival.

Project description:NMDA receptor (NMDAR) stimulation promotes neuronal survival during brain development. Cerebellar granule cells (CGCs) need NMDAR stimulation to survive and develop. These neurons differentiate and mature during its migration from the external granular layer to the internal granular layer, and lack of excitatory inputs triggers their apoptotic death. It is possible to mimic this process in vitro by culturing CGCs in low KCl concentrations (5 mm) in the presence or absence of NMDA. Using this experimental approach, we have obtained whole genome expression profiles after 3 and 8 h of NMDA addition to identify genes involved in NMDA-mediated survival of CGCs. One of the identified genes was Nurr1, a member of the orphan nuclear receptor subfamily Nr4a. Our results report a direct regulation of Nurr1 by CREB after NMDAR stimulation. ChIP assay confirmed CREB binding to Nurr1 promoter, whereas CREB shRNA blocked NMDA-mediated increase in Nurr1 expression. Moreover, we show that Nurr1 is important for NMDAR survival effect. We show that Nurr1 binds to Bdnf promoter IV and that silencing Nurr1 by shRNA leads to a decrease in brain-derived neurotrophic factor (BDNF) protein levels and a reduction of NMDA neuroprotective effect. Also, we report that Nurr1 and BDNF show a similar expression pattern during postnatal cerebellar development. Thus, we conclude that Nurr1 is a downstream target of CREB and that it is responsible for the NMDA-mediated increase in BDNF, which is necessary for the NMDA-mediated prosurvival effect on neurons.

| S-EPMC3322860 | biostudies-literature

NR2B-NMDA receptor mediated modulation of the tyrosine phosphatase STEP regulates glutamate induced neuronal cell death.

Project description:The present study examines the role of a neuron-specific tyrosine phosphatase (STEP, striatal-enriched tyrosine phosphatase) in excitotoxic cell death. Our findings demonstrate that p38 MAPK, a stress-activated kinase that is known to play a role in the etiology of excitotoxic cell death is a substrate of STEP. Glutamate-mediated NMDA receptor stimulation leads to rapid but transient activation of p38 MAPK, which is primarily dependent on NR2A-NMDA receptor activation. Conversely, activation of NR2B-NMDA receptors leads to dephosphorylation and subsequent activation of STEP, which in turn leads to inactivation of p38 MAPK. Thus, during transient NMDA receptor stimulation, increases in STEP activity appears to limit the duration of activation of p38 MAPK and improves neuronal survival. However, if NR2B-NMDA receptor stimulation is sustained, protective effects of STEP activation are lost, as these stimuli cause significant degradation of active STEP, leading to secondary activation of p38 MAPK. Consistent with this observation, a cell transducible TAT-STEP peptide that constitutively binds to p38 MAPK attenuated neuronal cell death caused by sustained NMDA receptor stimulation. The findings imply that the activation and levels of STEP are dependent on the duration and magnitude of NR2B-NMDA receptor stimulation and STEP serves as a modulator of NMDA receptor dependent neuronal injury, through its regulation of p38 MAPK.

| S-EPMC3035421 | biostudies-literature

CXCL12 inhibits expression of the NMDA receptor's NR2B subunit through a histone deacetylase-dependent pathway contributing to neuronal survival.

Project description:Homeostatic chemokines, such as CXCL12, can affect neuronal activity by the regulation of inhibitory and excitatory neurotransmission, but the mechanisms involved are still undefined. Our previous studies have shown that CXCL12 protects cortical neurons from excitotoxicity by promoting the function of the gene-repressor protein Rb, which is involved in the recruitment of chromatin modifiers (such as histone deacetylases (HDACs)) to gene promoters. In neurons, Rb controls activity-dependent genes essential to neuronal plasticity and survival, such as the N-methyl-D-aspartic acid (NMDA) receptor's subunit NR2B, the expression of which in the tetrameric ion channel largely affects calcium signaling by glutamate. In this study, we report that CXCL12 differentially modulates intracellular responses after stimulation of synaptic and extrasynaptic NMDA receptors, by a specific regulation of the NR2B gene that involves HDACs. Our results show that CXCL12 selectively inhibits NR2B expression in vitro and in vivo altering NMDA-induced calcium responses associated with neuronal death, while promoting prosurvival pathways that depend on stimulation of synaptic receptors. Along with previous studies, these findings underline the role of CXCL12/CXCR4 in the regulation of crucial components of glutamatergic transmission. These novel effects of CXCL12 may be involved in the physiological function of the chemokine in both developing and mature brains.

| S-EPMC3032300 | biostudies-literature

Caffeine inhibits hypoxia-induced nuclear accumulation in HIF-1? and promotes neonatal neuronal survival.

Project description:Apnea of prematurity (AOP) defined as cessation of breathing for 15-20?s, is commonly seen in preterm infants. Caffeine is widely used to treat AOP due to its safety and effectiveness. Caffeine releases respiratory arrest by competing with adenosine for binding to adenosine A1 and A2A receptors (A1R and A2AR). Long before its use in treating AOP, caffeine has been used as a psychostimulant in adult brains. However, the effect of caffeine on developing brains remains unclear. We found that A1R proteins for caffeine binding were expressed in the brains of neonatal rodents and preterm infants (26-27?weeks). Neonatal A1R proteins colocalized with PSD-95, suggesting its synaptic localization. In contrast, our finding on A2R expression in neonatal neurons was restricted to the mRNA level as detected by single cell RT/PCR due to the lack of specific A2AR antibody. Furthermore, caffeine (200??M) at a dose twice higher than the clinically relevant dose (36-130??M) had minor or no effects on several basic neuronal functions, such as neurite outgrowth, synapse formation, expression of A1R and transcription of CREB-1 and c-Fos, further supporting the safety of caffeine for clinical use. We found that treatment with CoCl2 (125??M), a hypoxia mimetic agent, for 24?h triggered neuronal death and nuclear accumulation of HIF-1? in primary neuronal cultures. Subsequent treatment with caffeine at a concentration of 100??M alleviated CoCl2-induced cell death and prevented nuclear accumulation of HIF-1?. Consistently, caffeine treatment in early postnatal life of neonatal mice (P4-P7) also prevented subsequent hypoxia-induced nuclear increase of HIF-1?. Together, our data support the utility of caffeine in alleviating hypoxia-induced damages in developing neurons.

| S-EPMC6935249 | biostudies-literature

DeltaNp73 modulates nerve growth factor-mediated neuronal differentiation through repression of TrkA.

Project description:p73, a member of the p53 family, expresses two classes of proteins: the full-length TAp73 and the N-terminally truncated DeltaNp73. While TAp73 possesses many p53-like features, DeltaNp73 is dominant negative towards TAp73 and p53 and appears to have distinct functions in tumorigenesis and neuronal development. Given its biological importance, we investigated the role of DeltaNp73 in nerve growth factor (NGF)-mediated neuronal differentiation in PC12 cells. We show that overexpression of DeltaNp73alpha or DeltaNp73beta inhibits NGF-mediated neuronal differentiation in both p53-dependent and -independent manners. In line with this, we showed that the level of endogenous DeltaNp73 is progressively diminished in differentiating PC12 cells upon NGF treatment and knockdown of DeltaNp73 promotes NGF-mediated neuronal differentiation. Interestingly, we found that the ability of DeltaNp73 to suppress NGF-mediated neuronal differentiation is correlated with its ability to regulate the expression of TrkA, the high-affinity NGF receptor. Specifically, we found that DeltaNp73 directly binds to the TrkA promoter and transcriptionally represses TrkA expression, which in turn attenuates the NGF-mediated mitogen-activated protein kinase pathway. Conversely, the steady-state level of TrkA is increased upon knockdown of DeltaNp73. Furthermore, we found that histone deacetylase 1 (HDAC1) and HDAC2 are recruited by DeltaNp73 to the TrkA promoter and act as corepressors to suppress TrkA expression, which can be relieved by trichostatin A, an HDAC inhibitor. Taken together, we conclude that DeltaNp73 negatively regulates NGF-mediated neuronal differentiation by transrepressing TrkA.

| S-EPMC1899982 | biostudies-literature

Stress-Induced Neuronal Colony Stimulating Factor 1 Provokes Microglia-Mediated Neuronal Remodeling and Depressive-like Behavior.

Project description:BackgroundChronic stress exposure causes neuronal atrophy and synaptic deficits in the medial prefrontal cortex (PFC), contributing to development of anxiety- and depressive-like behaviors. Concomitantly, microglia in the PFC undergo morphological and functional changes following stress exposure, suggesting that microglia contribute to synaptic deficits underlying behavioral consequences.MethodsMale and female mice were exposed to chronic unpredictable stress (CUS) to examine the role of neuron-microglia interactions in the medial PFC during development of anxiety- and depressive-like behaviors. Thy1-GFP-M mice were used to assess microglia-mediated neuronal remodeling and dendritic spine density in the medial PFC. Viral-mediated knockdown of neuronal colony stimulating factor 1 (CSF1) was used to modulate microglia function and behavioral consequences after CUS.ResultsCUS promoted anxiety- and depressive-like behaviors that were associated with increased messenger RNA levels of CSF1 in the PFC. Increased CSF1 messenger RNA levels were also detected in the postmortem dorsolateral PFC of individuals with depression. Moreover, microglia isolated from the frontal cortex of mice exposed to CUS show elevated CSF1 receptor expression and increased phagocytosis of neuronal elements. Notably, functional alterations in microglia were more pronounced in male mice compared with female mice. These functional changes in microglia corresponded with reduced dendritic spine density on pyramidal neurons in layer 1 of the medial PFC. Viral-mediated knockdown of neuronal CSF1 in the medial PFC attenuated microglia-mediated neuronal remodeling and prevented behavioral deficits caused by CUS.ConclusionsThese findings revealed that stress-induced elevations in neuronal CSF1 provokes microglia-mediated neuronal remodeling in the medial PFC, contributing to synaptic deficits and development of anxiety- and depressive-like behavior.

| S-EPMC6506225 | biostudies-literature

Suppressed nuclear factor-kappa B alleviates lipopolysaccharide-induced acute lung injury through downregulation of CXCR4 mediated by microRNA-194.

Project description:Acute lung injury (ALI) is a highly lethal pulmonary disease that causes edema, hypoxemia and respiratory failure. Recent evidence indicates that nuclear factor-kappa B (NF-?B) plays a crucial role in ALI development. However, the regulatory mechanism of NF-?B on ALI remains enigmatic. In this study, we investigated potential molecular mechanism of NF-?B on ALI induced by lipopolysaccharide (LPS). BALB/c mice were subjected to intratracheal spraying of LPS to generate an ALI mode, with the activity of NF-?B in mice tissues being detected by enzyme linked immunosorbent assay (ELISA), and the number of inflammatory cells in bronchoalveolar lavage fluid being counted. Then, the macrophage cell line RAW264.7 exposed to LPS were treated with ammonium pyrrolidinedithiocarbamate (PDTC) (inhibitor of NF-?B), miR-194 mimic, or oe-chemokine receptor type 4 (CXCR4) separately or in combination. After that, ELISA and reverse transcription quantitative polymerase chain reaction (RT-qPCR) were used to detect the expression level of IL-1?, IL-6, TNF-?, miR-194 and CXCR4, respectively. In addition, the targeting relationship between miR-194 and CXCR4 was verified by dual-luciferase reporter gene assay. The dry/wet ratio of lung and the MPO activity were also measured to assess the inflammatory response in mice. Activation of NF-?B down-regulated the miR-194 expression in LPS-induced ALI. Overexpression of miR-194 alleviated LPS-induced ALI and reduced the expression of inflammatory factors IL-1?, IL-6 and TNF-? via targeting CXCR4. In LPS-induced ALI, NF-?B mediates the CXCR4 expression by inhibiting the expression of miR-194, thus promoting the inflammatory injury of lung.

| S-EPMC7288420 | biostudies-literature

NMDA Receptors Enhance Spontaneous Activity and Promote Neuronal Survival in the Developing Cochlea.

Project description:Spontaneous bursts of activity in developing sensory pathways promote maturation of neurons, refinement of neuronal connections, and assembly of appropriate functional networks. In the developing auditory system, inner hair cells (IHCs) spontaneously fire Ca(2+) spikes, each of which is transformed into a mini-burst of action potentials in spiral ganglion neurons (SGNs). Here we show that NMDARs are expressed in SGN dendritic terminals and play a critical role during transmission of activity from IHCs to SGNs before hearing onset. NMDAR activation enhances glutamate-mediated Ca(2+) influx at dendritic terminals, promotes repetitive firing of individual SGNs in response to each synaptic event, and enhances coincident activity of neighboring SGNs that will eventually encode similar frequencies of sound. Loss of NMDAR signaling from SGNs reduced their survival both in vivo and in vitro, revealing that spontaneous activity in the prehearing cochlea promotes maturation of auditory circuitry through periodic activation of NMDARs in SGNs.

| S-EPMC4724245 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data