Abnormalities in Prefrontal Cortical Gene Expression Profiles Relevant to Schizophrenia in MK801-Exposed C57BL/6 Mice.
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE111708 | GEO | 2019/03/12
REPOSITORIES: GEO
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Project description:Deciphering the molecular pathways associated with N-methyl-D-aspartate receptor (NMDAr) hypofunction and its interaction with antipsychotics is necessary to advance our understanding of the basis of schizophrenia, as well as our capacity to treat this disease. In this regard, the development of human brain-derived models amenable for studying the neurobiology of schizophrenia may contribute to fill the gaps led by the widely employed animal models. Here we assessed the proteomic changes induced by the NMDA glutamate receptor antagonist MK-801 on human brain slice cultures obtained from adult donors submitted to resective neurosurgery. Initially, we demonstrated that MK-801 diminishes NMDA glutamate receptor signaling in human brain slices in culture. Next, using mass- spectrometry-based proteomics and systems biology in silico analyses, we found that MK-801 led to alterations in proteins related to several pathways previously associated with schizophrenia pathophysiology including ephrin, opioid, melatonin, sirtuin signaling, interleukin 8, endocannabinoid and synaptic vesicle cycle. We also evaluated the impact of both typical and atypical antipsychotics on MK-801-induced proteome changes. Interestingly, the atypical antipsychotic clozapine showed a more significant capacity to counteract the protein alterations induced by NMDAr hypofunction than haloperidol. Finally, using our dataset we identified potential modulators of the MK-801-induced proteome changes, which may be considered promising targets to treat NMDAr hypofunction in schizophrenia.
2024-02-06 | PXD046944 | Pride
Project description:N-Methyl-D-aspartate receptors (NMDAr), widely located around the central nervous system, are known to be involved in behavioral disorders. Dizocilpine (commonly referred to as MK-801) is a well known non-competitive NMDAr antagonist. We treated rats with intraperitoneal injection [0.08 (low-dose) and 0.16 (high-dose) mg/kg] of MK-801. In one experiment, 40 min after NaCl (vehicle control) and MK-801 (0.08 mg/kg) injection, electrocorticogram (ECoG) signals were analyzed. In the second experiment, 40 min post-injection, the whole brain of each animal was rapidly removed and separated into amyglada, cerebral cortex, hippocampus, hypothalamus, midbrain and ventral striatum) on ice, followed by analysis using a 4x44K DNA microarray chip. Spectral analysis revealed that a single systemic injection of MK-801 significantly and selectively augmented the power of baseline (30-80 Hz) frequency oscillations. DNA microarray analysis showed the largest number (up- and down- regulations) of gene expressions in the cerebral cortex (378), midbrain (376), hippocampus (375), ventral striatum (353), amygdala (301), and hypothalamus (201) under low-dose of MK-801. Under high-dose, ventral striatum (811) showed the largest number of gene expression changes. Gene expression changes were functionally categorized to reveal expression of genes and function varies with each brain region. MK-801 increases the synchrony of baseline oscillations, causing very early changes in gene expressions in rat brain after acute MK-801 treatment, a first report. The overall goal of the present study was to identify gene expression patterns along rat chromosomes in different brain regions after a single injection of MK-801, which exerts a longer acute effect than ketamine on ongoing brain activities. Two approaches were taken, first electrophysiological and send molecular analysis, where the brain of MK-801-treated rats was subjected to a genome-wide transcriptome mapping analysis (~4400 genes) in the cerebral cortex, midbrain, hippocampus, ventral striatum, amygdala, and hypothalamus regions.
2014-11-26 | E-GEOD-63639 | biostudies-arrayexpress
Project description:N-Methyl-D-aspartate receptors (NMDAr), widely located around the central nervous system, are known to be involved in behavioral disorders. Dizocilpine (commonly referred to as MK-801) is a well known non-competitive NMDAr antagonist. We treated rats with intraperitoneal injection [0.08 (low-dose) and 0.16 (high-dose) mg/kg] of MK-801. In one experiment, 40 min after NaCl (vehicle control) and MK-801 (0.08 mg/kg) injection, electrocorticogram (ECoG) signals were analyzed. In the second experiment, 40 min post-injection, the whole brain of each animal was rapidly removed and separated into amyglada, cerebral cortex, hippocampus, hypothalamus, midbrain and ventral striatum) on ice, followed by analysis using a 4x44K DNA microarray chip. Spectral analysis revealed that a single systemic injection of MK-801 significantly and selectively augmented the power of baseline (30-80 Hz) frequency oscillations. DNA microarray analysis showed the largest number (up- and down- regulations) of gene expressions in the cerebral cortex (378), midbrain (376), hippocampus (375), ventral striatum (353), amygdala (301), and hypothalamus (201) under low-dose of MK-801. Under high-dose, ventral striatum (811) showed the largest number of gene expression changes. Gene expression changes were functionally categorized to reveal expression of genes and function varies with each brain region. MK-801 increases the synchrony of baseline oscillations, causing very early changes in gene expressions in rat brain after acute MK-801 treatment, a first report.
2014-11-26 | GSE63639 | GEO
Project description:Synaptic dysfunction has been implicated in the pathogenesis of schizophrenia (SCZ) and bipolar disorder (BP). In this study, we used quantitative mass-spectrometry to carry out deep and unbiased profiling of the proteome of synapses purified from the dorsolateral prefrontal cortex of 35 controls and 35 cases each with SCZ or BP. Compared to controls, SCZ and BP synapses showed substantial and similar proteomic alterations. Network and gene set enrichment analyses revealed upregulation of proteins associated with autophagy and certain vesicle transport pathways, and downregulation of proteins related to synaptic, mitochondrial, and ribosomal function in the synapses of individuals with SCZ or BP. We also uncovered evidence for dysregulation of some of the same pathways (e.g., upregulation of vesicle transport, downregulation of mitochondrial and ribosomal proteins) in the synaptic proteome of mutant mice deficient in Akap11, a recently discovered risk gene for both SCZ and BP. Our work provides novel biological insights and hypotheses into molecular dysfunction at the synapse in SCZ and BP and serves as a resource for understanding the pathophysiology of these debilitating neuropsychiatric disorders.
| MSV000090320 | MassIVE
Project description:Background: N-Methyl-D-aspartate receptors (NMDAr), widely located around the central nervous system, are known to be involved in behavioral disorders. Dizocilpine (commonly referred to as MK-801) is a well known non-competitive NMDAr antagonist. Methods: We treated rats with intraperitoneal injection [0.08 (low-dose) and 0.16 (high-dose) mg/kg] of MK-801. In one experiment, 40 min after NaCl (vehicle control) and MK-801 (0.08 mg/kg) injection, electrocorticogram (ECoG) signals were analyzed. In the second experiment, 40 min post-injection, the whole brain of each animal was rapidly removed and separated into amyglada, cerebral cortex, hippocampus, hypothalamus, midbrain and ventral striatum) on ice, followed by analysis using a 4x44K DNA microarray chip. Results: Spectral analysis revealed that a single subcutaneous injection of MK-801 significantly and selectively augmented the power of spontaneous gamma and higher-frequency oscillations. The results from DNA microarray analysis of 4400 genes showed the largest number (up- and down- regulations) of gene expressions in the cerebral cortex (378), midbrain (376), hippocampus (375), ventral striatum (353), amygdala (301), and hypothalamus (201) under low-dose of MK-801. Under high-dose, ventral striatum (811) showed the largest number of gene expression changes. These genes represented... Conclusions: Our results reveal that MK-801 triggered i) an increase in the power of gamma oscillations, and ii) simultaneously caused very early changes in gene expressions in the rat brain, representing a first such inventory of gene expression profiles in brain after acute MK-801 treatment.
2012-04-25 | GSE37413 | GEO
Project description:Background: N-Methyl-D-aspartate receptors (NMDAr), widely located around the central nervous system, are known to be involved in behavioral disorders. Dizocilpine (commonly referred to as MK-801) is a well known non-competitive NMDAr antagonist. Methods: We treated rats with intraperitoneal injection [0.08 (low-dose) and 0.16 (high-dose) mg/kg] of MK-801. In one experiment, 40 min after NaCl (vehicle control) and MK-801 (0.08 mg/kg) injection, electrocorticogram (ECoG) signals were analyzed. In the second experiment, 40 min post-injection, the whole brain of each animal was rapidly removed and separated into amyglada, cerebral cortex, hippocampus, hypothalamus, midbrain and ventral striatum) on ice, followed by analysis using a 4x44K DNA microarray chip. Results: Spectral analysis revealed that a single subcutaneous injection of MK-801 significantly and selectively augmented the power of spontaneous gamma and higher-frequency oscillations. The results from DNA microarray analysis of 4400 genes showed the largest number (up- and down- regulations) of gene expressions in the cerebral cortex (378), midbrain (376), hippocampus (375), ventral striatum (353), amygdala (301), and hypothalamus (201) under low-dose of MK-801. Under high-dose, ventral striatum (811) showed the largest number of gene expression changes. These genes represented... Conclusions: Our results reveal that MK-801 triggered i) an increase in the power of gamma oscillations, and ii) simultaneously caused very early changes in gene expressions in the rat brain, representing a first such inventory of gene expression profiles in brain after acute MK-801 treatment. Nine male 10-weeks-old Wistar rats (300-350 g BW) were housed in acrylic cages (3/cage) at 24ºC and given access to tap water and laboratory chow ad libitum. The rats were divided into two groups, and each group rats received i.p. injection of 0.08 (low-dose) and 0.16 (high-dose) mg/kg of MK-801, respectively. Three rats were treated with saline as sham (vehicle control group) using the same method. After 40 min post-injection, the whole brain of each animal was rapidly removed and put on ice, and brain regions were separated according to the method of Glowinski and Iversen (1996), with minor modifications (Hirano et al., 2007). Each brain region was placed in a 2 mL Eppendorf tube, quickly immersed in liquid nitrogen before being stored in -80ºC prior to further analysis. Each sample was immediately weighed, flash-frozen in liquid nitrogen and stored at -80ºC prior to further analysis. A rat 4 x 44K whole genome oligo DNA microarray chip (G4131F, Agilent Technologies, Palo Alto, CA, USA) was used for global gene expression analysis. The effects of MK-801 were examined in the 6 brain reagion, Ventral striatum, Cerebral cortex, Midbrain, Amygdala, Hippocampus, and Hypothalamus.
2012-04-24 | E-GEOD-37413 | biostudies-arrayexpress
Project description:We established PCCB knockdown human induced pluripotent stem cell (hiPSC) line using CRISPR interference (CRISPRi). The established PCCB knockdown and control hiPSCs were then used to generate human forebrain organoids (hFOs). On day 60 of organoid culture, PCCB knockdown and control hFOs were randomly selected for RNA-sequencing (RNA-seq). We found that differentially expressed genes (DEGs) affected by PCCB knockdown were enriched with GABAergic synapse, synaptic vesicle cycle, neurotransmitter transport, forebrain development, axon development, synaptic organization, and calcium signaling pathways. The DEGs were also significantly overlapped with schizophrenia (SCZ)-associated genes, including genes dysregulated in brains or organoids derived from SCZ patients, and genes reported in SCZ GWAS.
2023-05-02 | GSE226233 | GEO
Project description:Background: microRNAs (miRNAs) are small, non-coding RNAs, which can silence the expression of various target genes via binding their mRNAs, thus miRNAs serve and regulate a wide range of crucial functions in the body. However, the miRNAs expression profile after the antipsychotics mediation in schizophrenia is largely unknown. Methods: Noncompetitive N-methyl-D-aspartic acid (NMDA) receptor antagonists like as MK-801 had been shown to provide a useful animal model to investigate these effects of schizophrenia-like symptoms in rodent animals. In this study, the rat hippocampal miRNA expression profiles were examined after the antipsychotic clozapine (CLO) treated the MK-801-pretreated Sprague Dawley rats. The total RNA samples from their hippocampus of three rat groups were sequenced using next generation sequencing (NGS), then processed bioinformatic analysis. Results: Successfully, we identified 8 miRNAs’ expressions were significantly different in the MK-801 group comparing the VEH control group. Interestingly, 14 miRNAs were largely changed expression in CLO+MK-80-treated group comparing the MK-801-pretreated group, in which the rno-miR-184 was up-regulated significantly. Subsequently, further analyses suggested these miRNAs could modulate their target genes involving in the regulation of endocytosis, ubiquitin mediated proteolysis and regulation of actin cytoskeleton, which might be involved in the important mechanism of schizophrenia. Conclusion: Our results suggested the altered miRNA expressions might play an important role in the complex pathophysiology of schizophrenia, and subsequently impacted on brain functions.
2020-10-01 | GSE129466 | GEO
Project description:Genome-wide association studies indicate allele variants in MIR137, the host gene of microRNA-137 (miR137), confer an increased risk of schizophrenia (SCZ). Expression of miR137 and its targets, many of which regulate synaptic functioning, are also associated with an increased risk of SCZ. As a result, miR137 represents an attractive target aimed at correcting the molecular basis for synaptic dysfunction in individuals with high genetic risk for SCZ. Advancements in nanotechnology utilize lipid nanoparticles (LNPs) to transport and deliver therapeutic RNA. However, there remains a gap in using LNPs to regulate gene and protein expression in the brain. To study the delivery of nucleic acids by LNPs to the brain, we found that LNPs released miR137 cargo and inhibited synaptic target transcripts in neuronal cultures. Biodistribution of LNPs loaded with firefly luciferase mRNA remained localized to the mouse prefrontal cortex (PFC) injection site without circulating to off-target organs. LNPs encapsulating Cre mRNA preferentially co-expressed in neuronal over microglial or astrocytic cells. Using quantitative proteomics, we found miR137 modulated glutamatergic synaptic protein networks that are commonly dysregulated in SCZ. These studies support engineering the next generation of brain-specific LNPs to deliver personalized RNA therapeutics and improve symptoms of central nervous system disorders.
2023-09-05 | PXD041648 | Pride
Project description:Schizophrenia typically emerges in adolescence or early adulthood. Electrophysiological and several neurochemical changes have linked the GABA deficits to abnormal behaviors induced by NMDAR hypofunction. However, few studies have systematically investigated the molecular basis of GABA deficits, especially during adolescence. To address this issue, we transiently administrated MK-801 to mice on PND 10, which exhibited schizophrenia-relevant deficits in adolescence. Saline treated mice was served as controls. Cortical proteomics was performed on adolescent mice to investigate the proteome alteration.
2022-07-05 | PXD035089 |