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Regulation of neuronal gene expression and survival by basal NMDA receptor activity: a role for Histone Deacetylase 4

ABSTRACT: Gene expression analysisis of NR2A and NR2B containing NMDA receptors after treatment with AP5, NVP-AAM077 and Ro25-6981

ORGANISM(S): Mus musculus

PROVIDER: GSE54708 | GEO | 2014/10/23

SECONDARY ACCESSION(S): PRJNA237463

REPOSITORIES: GEO

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Regulation of neuronal gene expression and survival by basal NMDA receptor activity: a role for Histone Deacetylase 4

Project description:Gene expression analysisis of NR2A and NR2B containing NMDA receptors after treatment with AP5, NVP-AAM077 and Ro25-6981 4 conditions, vehicle, AP5, Ro25, and NVP, 4-5 replicates of each sample

2014-10-23 | E-GEOD-54708 | biostudies-arrayexpress

Neuronal activity stimulates astrocyte proliferation through NMDA receptor-dependent induction of Prostaglandin-Endoperoxide Synthase 2

Project description:Gene expression analysisis of NR2A and NR2B containing NMDA receptors after treatment with AP5, NVP-AAM077 and Ro25-6981

2022-11-01 | GSE89802 | GEO

Regulation of neuronal gene expression and survival by basal NMDA receptor activity: a role for histone deacetylase 4.

Project description:Neuronal gene expression is modulated by activity via calcium-permeable receptors such as NMDA receptors (NMDARs). While gene expression changes downstream of evoked NMDAR activity have been well studied, much less is known about gene expression changes that occur under conditions of basal neuronal activity. In mouse dissociated hippocampal neuronal cultures, we found that a broad NMDAR antagonist, AP5, induced robust gene expression changes under basal activity, but subtype-specific antagonists did not. While some of the gene expression changes are also known to be downstream of stimulated NMDAR activity, others appear specific to basal NMDAR activity. The genes altered by AP5 treatment of basal cultures were enriched for pathways related to class IIa histone deacetylases (HDACs), apoptosis, and synapse-related signaling. Specifically, AP5 altered the expression of all three class IIa HDACs that are highly expressed in the brain, HDAC4, HDAC5, and HDAC9, and also induced nuclear accumulation of HDAC4. HDAC4 knockdown abolished a subset of the gene expression changes induced by AP5, and led to neuronal death under long-term tetrodotoxin or AP5 treatment in rat hippocampal organotypic slice cultures. These data suggest that basal, but not evoked, NMDAR activity regulates gene expression in part through HDAC4, and, that HDAC4 has neuroprotective functions under conditions of low NMDAR activity.

| S-EPMC4228135 | biostudies-literature

NMDA receptor positive allosteric modulator induced genome wide gene expression changes in neuronal cultures

Project description:To investigate genome-wide gene expression changes induced by an NMDA receptor positive allosteric modulator in neuronal cultures using next-generation sequencing

2021-01-01 | GSE139080 | GEO

GLP-1 directed NMDA receptor antagonism for obesity treatment [I]

Project description:The N-methyl-d-aspartate (NMDA) receptor is a glutamate-activated cation channel critical to many processes in the brain. Genome-wide association studies (GWAS) suggest that glutamatergic neurotransmission and NMDA receptor-mediated synaptic plasticity is important for body weight homeostasis1. Here, we report the engineering and preclinical development of a first-in-class bimodal molecule that integrates NMDA receptor antagonism with glucagon-like peptide-1 (GLP-1) receptor agonism to effectively reverse obesity, hyperglycemia, and dyslipidemia in rodent models of metabolic disease. We demonstrate that GLP-1-directed delivery of the NMDA receptor antagonist MK-801 affects NMDA receptor-mediated synaptic plasticity in the hypothalamus. Importantly, peptide-targeting of MK-801 specifically to GLP-1 receptor-expressing brain regions circumvent adverse physiological and behavioral effects associated with MK-801 monotherapy. In sum, our approach demonstrates the feasibility of cell specific ionotropic receptor-modulation via peptide targeting and highlights the therapeutic potential of unimolecular mixed GLP-1 receptor agonism and NMDA receptor antagonism for obesity treatment.

2024-05-14 | GSE244607 | GEO

GLP-1 directed NMDA receptor antagonism for obesity treatment [II]

2024-05-14 | GSE245727 | GEO

GLP-1 directed NMDA receptor antagonism for obesity treatment

Project description:The N-methyl-D-aspartate (NMDA) receptor is a glutamate-activated cation channel critical to many processes in the brain. Genome-wide association studies (GWAS) suggest that glutamatergic neurotransmission and NMDA receptor-mediated synaptic plasticity is important for body weight homeostasis1. Here, we report the engineering and preclinical development of a first-in-class bimodal molecule that integrates NMDA receptor antagonism with glucagon-like peptide-1 (GLP-1) receptor agonism to effectively reverse obesity, hyperglycemia, and dyslipidemia in rodent models of metabolic disease. We demonstrate that GLP-1-directed delivery of the NMDA receptor antagonist MK-801 affects NMDA receptor-mediated synaptic plasticity in the hypothalamus. Importantly, peptide-targeting of MK-801 specifically to GLP-1 receptor-expressing brain regions circumvent adverse physiological and behavioral effects associated with MK-801 monotherapy. In sum, our approach demonstrates the feasibility of cell specific ionotropic receptor-modulation via peptide targeting and highlights the therapeutic potential of unimolecular mixed GLP-1 receptor agonism and NMDA receptor antagonism for obesity treatment.

2024-04-26 | PXD045816 | Pride

Effects of developmental N-Methyl D-aspartate (NMDA) receptor antagonism on adulthood hypothalamic gene expression in female C57Bl/6J mice.

Project description:AIM: to examine changes in hypothalamic gene expression following developmental N-Methyl D-aspartate (NMDA) receptor antagonism in adult female C57Bl/6J mice. AIM: to examine changes in hypothalamic gene expression following developmental N-Methyl D-aspartate (NMDA) receptor antagonism in adult female C57Bl/6J mice. This data will compliment on-going studies into the effect of developmental NMDA receptor antagonism on aspects of the Hypothalamic-Pituitary-Adrenal (HPA) axis.

2019-12-13 | GSE108042 | GEO

GLP-1 directed NMDA receptor antagonism for obesity treatment

Project description:GLP-1 directed NMDA receptor antagonism for obesity treatment

| PRJNA1029620 | ENA

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

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