Zinc-dependent gene expression in neurons upon glutamate stimulation
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ABSTRACT:
PROVIDER: PRJNA595846 | ENA |
REPOSITORIES: ENA
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Project description:Zinc (Zn2+) has been increasingly recognized to function as an important neurotransmitter, although how it functions in the context of signaling cascades is as yet unknown. In dissociated rat hippocampal neuron cultures, we stimulated neurons with glutamate, with or without additional exogenous ZnCl2 or a cell-permeable zinc chelator TPA. We found considerable heterogeneity among biological replicates which complicated zinc-dependent gene expression analysis. In general, we saw upregulation of genes implicating ER stress in glutamate-stimulated neurons that experience a zinc signal.
2019-12-17 | GSE142064 | GEO
Project description:Glutamate is a major excitatory neurotransmitter in the nervous system. Increased and persistent release of glutamate is toxic to neurons and this excitotoxicity is a hallmark of several neurodegenerative diseases. Here, we use GRO-seq to screen for the acute transcriptional changes induced by glutamate exposure on embryonic mouse cortical neurons to reveal downstream molecules which could participate in glutamate-induced toxicity. We show that several miRNA genes, such as miR-21, have altered expression upon glutamate exposure.
2023-01-03 | GSE215210 | GEO
Project description:Excitotoxicity caused by over-stimulation of the ionotropic glutamate receptors is a key neuronal cell death process underpinning brain damage in acute and chronic neurological disorders such as ischaemic stroke, traumatic brain injury, and neurodegenerative diseases. Exactly how neurons die in excitotoxicity still remains unclear and is an important area of research in the field of neuroscience. In this current project we wanted to explore the global changes in proteome and phosphoproteome following glutamate excitotoxicity in cultured primary cortical neurons.
2019-03-07 | PXD008353 | Pride
Project description:Cutaneous mast cells (MC) mediate numerous skin inflammatory processes and have anatomical and functional associations with sensory afferent neurons. We found that Langerhans cell (LC)-deficient mice have reduced numbers of MrgprD-expressing epidermal nerve endings and manifest enhanced irritant dermatitis due to exaggerated MC degranulation. Ablation of LC or MrgprD-expressing neurons increased expression of a MC gene module including the activating receptor, Mrgprb2, resulting in increased MC degranulation and cutaneous inflammation in multiple models. β-alanine agonism of MrgprD-expressing neurons reduced expression of MC module genes and suppressed MC responses. MrgprD-expressing neurons released glutamate which was increased by MrgprD agonism and decreased in LC-deficient mice. Inhibiting glutamate release or glutamate receptor binding yielded hyperresponsive MC and a genomic state similar to that in mice lacking MrgprD-expressing neurons. These data demonstrate that MrgprD-expressing neurons suppress MC hyperresponsiveness and skin inflammation via glutamate release thereby revealing an unexpected neuro-immune mechanism maintaining cutaneous immune homeostasis.
2021-03-23 | GSE165295 | GEO
Project description:<p>Tet3 is the main α-ketoglutarate (αKG)-dependent dioxygenase in neurons that converts 5-methyl-dC into 5-hydroxymethyl-dC and further on to 5-formyl- and 5-carboxy-dC. Neurons possess high levels of 5-hydroxymethyl-dC that further increase during neural activity to establish transcriptional plasticity required for learning and memory functions. How αKG, which is mainly generated in mitochondria as an intermediate of the tricarboxylic acid cycle, is made available in the nucleus has remained an unresolved question in the connection between metabolism and epigenetics. We show that in neurons the mitochondrial enzyme glutamate dehydrogenase, which converts glutamate into αKG in an NAD+-dependent manner, is redirected to the nucleus by the αKG-consumer protein Tet3, suggesting on-site production of αKG. Further, glutamate dehydrogenase has a stimulatory effect on Tet3 demethylation activity in neurons, and neuronal activation increases the levels of αKG. Overall, the glutamate dehydrogenase-Tet3 interaction might have a role in epigenetic changes during neural plasticity.</p><p><br></p>
2021-06-24 | MTBLS2852 | MetaboLights
Project description:A substantial proportion of basal amygdala (BA) glutamate neurons project to nucleus accumbens (NAc). The evidence that these neurons are activated by reward and/or aversion is equivocal. Social stimuli are highly salient, and in male mice we conducted a detailed analysis of the responsiveness of BA-NAc neurons to estrous female (social reward, SR) or aggressive male (social aversion, SA). Both SR and SA activated c-Fos expression in a relatively high number of BA-NAc neurons in intermediate (int) BA. Using Fos-TRAP2 mice, the majority of social int-BA-NAc neurons were activated by either SR or SA, i.e. were monovalent, and in similar numbers. Fiber photometry provided corroborative evidence that int-BA-NAc neural pathway activity was similar in response to SR or SA. These findings contribute substantially to understanding the topography and valence-specificity of BA-NAc neurons with respect to highly salient stimuli, and to identifying molecular targets for treatment of reward- or aversion-specific psychopathologies.
2023-12-17 | GSE220269 | GEO
Project description:Spinocerebellar ataxias 2 and 3 (SCA2 and SCA3) are dominantly inherited neurodegenerative diseases caused by expansion of polyglutamine-encoding CAG repeats in the affected genes. The etiology of these disorders is known to involve widespread loss of neuronal cells in the cerebellum, however, the mechanisms that contribute to cell death are still elusive. Here we established SCA2 and SCA3 induced pluripotent stem cells (iPSCs) and demonstrated that SCA-associated pathological features can be recapitulated in SCA-iPSC-derived neurons. Importantly, our results also revealed that glutamate stimulation promotes the development of disease-related phenotypes in SCA-iPSC-derived neurons, including altered composition of glutamatergic receptors, destabilized intracellular calcium, and eventual cell death. Furthermore, anti-glutamate drugs and calcium stabilizer treatment protected the SCA-iPSC-derived neurons and reduced cell death. Collectively, our study demonstrates that the SCA-iPSC-derived neurons can recapitulate SCA-associated pathological features, providing a valuable tool to explore SCA pathogenic mechanisms and screen drugs to identify potential SCA therapeutics.
2019-02-14 | GSE96826 | GEO
Project description:Reduced reward interest/learning and reward-to-effort valuation are distinct, common symptoms in neuropsychiatric disorders for which chronic stress is a major aetiological factor. Pyramidal glutamate neurons in the basal amygdala (BA) project to various brain regions including nucleus accumbens (NAc). The BA-NAc neural pathway is activated by reward and aversion, with many neurons being monovalent. In adult male mice, chronic social stress (CSS) led to both reduced discriminative reward learning (DRL) associated with decreased BA-NAc Ca2+ activity, and reduced sucrose reward-to-effort valuation (REV) associated, in contrast, with increased BA-NAc Ca2+ activity. Chronic tetanus toxin inhibition of BA-NAc neurons replicated the CSS-DRL effect whilst causing only a mild REV reduction, whilst chronic DREADDs activation of BA-NAc neurons replicated the CSS effect on REV without affecting DRL. This study provides novel evidence that chronic stress disruption of reward processing involves the BA-NAc neural pathway; the bi-directional effects implicate activity changes in BA-NAc reward (learning) and aversion (effort) neurons, with the net overall direction of stress-induced change in activity dependent on on-going stimulus processing and behaviour.
2022-12-01 | GSE216588 | GEO
Project description:Primary cortical neurons were isolated from E15 mice and after 5 days in vitro were untreated or treated for 24 h with mesenchymal stem cell conditioned medium and then untreated or treated for a further 24 h with NMDA. Neuron gene expression was profiled and compared between the four different conditions (neurons, neurons+MSC cm, neurons+NMDA, neurons+MSC cm+NMDA) to investigate the molecular mechanisms of MSC neuroprotection. Mesenchymal stem cells (MSC) promote functional recovery in experimental models of central nervous system (CNS) pathology and are currently being tested in clinical trials for stroke, multiple sclerosis and CNS injury. Their beneficial effects are attributed to activation of endogenous CNS repair processes and immune regulation but their mechanisms of action are poorly understood. Here we investigated the neuroprotective effects of MSC in simplified MSC-neuron co-culture systems and in mice using models of glutamate excitotoxicity. MSC protected primary cortical neurons against glutamate (NMDA) receptor-induced death and conditioned medium from MSC (MSC cm), but not control NIH3T3 cells, was sufficient for this effect. MSC cm neuroprotection in mouse cortical neurons was reduced by neutralizing antibodies to bFGF and associated with altered gene expression in neurons towards an immature phenotype as well as reduced neuronal Grin1, Grin2a and Grin2b mRNA levels in response to NMDA stimulation. Further, MSC cm neuroprotection in rat retinal ganglion cells was associated with absence of glutamate-induced calcium influx. Adoptive transfer of EGFP+MSC in a mouse kainic acid seizure model reduced CA3 neuron damage and hippocampal astrocytosis and resulted in the increased expression of neuronal genes that are upregulated by MSC cm, Bmi1, Ddx4, Ezh1, in the hippocampus. These results show that MSC mediate direct neuroprotection against glutamate excitotoxicity by secreting bFGF, reducing glutamate receptor expression and function and altering neuron gene expression towards an immature pattern, and provide evidence for a link between the therapeutic effects of MSC and the activation of endogenous repair processes following CNS injury. In vitro cultures primary cortical neurons from mice were protected from glutamate excitotoxicity when pre-treated with MSC cm. Global gene expression changes induced in neurons before and after treatment with MSC cm and/or NMDA were investigated using a cDNA spotted macroarray filter. Four samples were analysed in duplicate: neurons alone (untreated), neurons+MSC cm, neurons+NMDA, neurons+MSC cm+NMDA.
2011-05-01 | E-GEOD-26279 | biostudies-arrayexpress
Project description:Changes in nascent transcripts upon glucocorticoid stimulation in macrophages
| PRJNA774825 | ENA