scholarly journals Reduction of Fmr1 mRNA Levels Rescues Pathological Features in Cortical Neurons in a Model of FXTAS

2019 ◽  
Vol 18 ◽  
pp. 546-553 ◽  
Author(s):  
Malgorzata Drozd ◽  
Sébastien Delhaye ◽  
Thomas Maurin ◽  
Sara Castagnola ◽  
Mauro Grossi ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Mrna Levels ◽  
Pathological Features ◽  
Fmr1 Mrna

scholarly journals Low Basal CB2R in Dopamine Neurons and Microglia Influences Cannabinoid Tetrad Effects

2020 ◽  
Vol 21 (24) ◽  
pp. 9763
Author(s):  
Qing-Rong Liu ◽  
Ana Canseco-Alba ◽  
Ying Liang ◽  
Hiroki Ishiguro ◽  
Emmanuel S. Onaivi
Keyword(s):  
Cortical Neurons ◽  
Cannabinoid Receptors ◽  
Dynamic Range ◽  
Conditional Knockout ◽  
Dopamine Neurons ◽  
In Vivo Studies ◽  
Mouse Strains ◽  
Genotypic Differences ◽  
Mrna Levels ◽  
Selective Agonist

There are two well-characterized cannabinoid receptors (CB1R and CB2R and other candidates): the central nervous system (CNS) enriched CB1R and peripheral tissue enriched CB2R with a wide dynamic range of expression levels in different cell types of human tissues. Hepatocytes and neurons express low baseline CB1R and CB2R, respectively, and their cell-type-specific functions are not well defined. Here we report inducible expression of CB1R in the liver by high-fat and high sugar diet and CB2R in cortical neurons by methamphetamine. While there is less controversy about hepatocyte CB1R, the presence of functional neuronal CB2R is still debated to date. We found that neuron CB2R basal expression was higher than that of hepatocyte CB1R by measuring mRNA levels of specific isoform CB2A in neurons isolated by fluorescence-activated cell sorting (FACS) and CB1A in hepatocytes isolated by collagenase perfusion of liver. For in vivo studies, we generated hepatocyte, dopaminergic neuron, and microglia-specific conditional knockout mice (Abl-Cnr1Δ, Dat-Cnr2Δ, and Cx3cr1-Cnr2Δ) of CB1R and CB2R by crossing Cnr1f/f and Cnr2f/f strains to Abl-Cre, Dat-Cre, and Cx3cr1-Cre deleter mouse strains, respectively. Our data reveals that neuron and microglia CB2Rs are involved in the “tetrad” effects of the mixed agonist WIN 55212-2, CB1R selective agonist arachidonyl-2′-chloroethylamide (ACEA), and CB2R selective agonist JWH133. Dat-Cnr2Δ and Cx3cr1-Cnr2Δ mice showed genotypic differences in hypomobility, hypothermia, analgesia, and catalepsy induced by the synthetic cannabinoids. Alcohol conditioned place preference was abolished in DAT-Cnr2Δ mice and remained intact in Cx3cr1-Cnr2Δ mice in comparison to WT mice. These Cre-loxP recombinant mouse lines provide unique approaches in cannabinoid research for dissecting the complex endocannabinoid system that is implicated in many chronic disorders.

scholarly journals 3′UTRs Regulate Mouse Ntrk2 mRNA Distribution in Cortical Neurons

2020 ◽  
Vol 70 (11) ◽  
pp. 1858-1870
Author(s):  
Shangqin Chen ◽  
Jinjin Zhu ◽  
Peijun Li ◽  
Zhaonan Xia ◽  
Mengjing Tu ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Cortical Neurons ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Mrna Levels ◽  
Tyrosine Kinase 2 ◽  
Mrna Transcripts ◽  
Cultured Cortical Neurons ◽  
Apical Dendrites

Abstract There are two major isoforms of NTRK2 (neurotrophic receptor tyrosine kinase 2, or TrkB), full-length isoform with tyrosine kinase (TK) domain intact (+) and spliced isoform without tyrosine kinase domain (TK(−)). Within each isoform, there exist subtypes with minor modifications of the protein sequences. In human, the NTRK2 mRNA transcripts encoding TK(+) have same 3′UTRs, while the transcripts encoding subtypes of NTRK2 TK(−) have two completely different 3′UTRs. In mouse, the mRNA transcripts encoding same NTRK2 protein sequence for either TK(+) or TK(−) have long or short 3′UTRs, respectively. The physiological functions of these different 3′UTRs are still unknown. Pilocarpine stimulation increased Ntrk2 mRNA levels in soma, while the increase in synaptosome was smaller. FISH results further showed that mouse Ntrk2 transcripts with different 3′UTRs were distributed differently in cultured cortical neurons. The transcripts with long 3′UTR were distributed more in apical dendrites compared with transcripts with short 3′UTR. Our results provide evidence of non-coding 3′UTR function in regulating mRNA distribution in neurons.

scholarly journals A novel enhancer that regulates Bdnf expression in developing neurons

2021 ◽  
Author(s):  
Emily Brookes ◽  
Ho Yu Alan Au ◽  
Wazeer Varsally ◽  
Christopher Barrington ◽  
Suzana Hadjur ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Neuronal Development ◽  
Nuclear Periphery ◽  
Mrna Levels ◽  
Bdnf Expression ◽  
Bdnf Mrna ◽  
Enhancer Activity ◽  
Mediated Effects ◽  
Developing Neurons ◽  
Activity Dependent

Brain derived neurotrophic factor (BDNF) is a critical secreted peptide that promotes neuronal differentiation and survival, and its downregulation is implicated in many neurological disorders. Here, we investigated the regulation of the mouse Bdnf gene in cortical neurons and identified a novel enhancer that promotes the expression of many Bdnf transcript variants during differentiation, increasing total Bdnf mRNA levels. Enhancer activity contributes to Bdnf-mediated effects on neuronal clustering and activity-dependent dendritogenesis. During Bdnf activation, enhancer-promoter contacts increase, and the region moves away from the repressive nuclear periphery. Our findings suggest that changes in nuclear structure may contribute to the expression of essential growth factors during neuronal development.

scholarly journals DNA Methylation at Birth Predicts Intellectual Functioning and Autism Features in Children with Fragile X Syndrome

2020 ◽  
Vol 21 (20) ◽  
pp. 7735
Author(s):  
Claudine M Kraan ◽  
Emma K Baker ◽  
Marta Arpone ◽  
Minh Bui ◽  
Ling Ling ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Single Gene ◽  
Intellectual Functioning ◽  
Dried Blood Spots ◽  
Reference Ranges ◽  
Mrna Levels ◽  
Blood Spots ◽  
Fmr1 Mrna

Fragile X syndrome (FXS) is a leading single-gene cause of intellectual disability (ID) with autism features. This study analysed diagnostic and prognostic utility of the Fragile X-Related Epigenetic Element 2 DNA methylation (FREE2m) assessed by Methylation Specific-Quantitative Melt Analysis and the EpiTYPER system, in retrospectively retrieved newborn blood spots (NBS) and newly created dried blood spots (DBS) from 65 children with FXS (~2–17 years). A further 168 NBS from infants from the general population were used to establish control reference ranges, in both sexes. FREE2m analysis showed sensitivity and specificity approaching 100%. In FXS males, NBS FREE2m strongly correlated with intellectual functioning and autism features, however associations were not as strong for FXS females. Fragile X mental retardation 1 gene (FMR1) mRNA levels in blood were correlated with FREE2m in both NBS and DBS, for both sexes. In females, DNAm was significantly increased at birth with a decrease in childhood. The findings support the use of FREE2m analysis in newborns for screening, diagnostic and prognostic testing in FXS.

Notoginsenoside R1 Promotes the Growth of Neonatal Rat Cortical Neurons via the Wnt/β-catenin Signaling Pathway

2018 ◽  
Vol 17 (7) ◽  
pp. 547-556 ◽  
Author(s):  
Xing-Tong Li ◽  
Wei Ma ◽  
Xian-Bin Wang ◽  
Zhang Liang ◽  
Jin-Wei Yang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Cortical Neurons ◽  
Wnt Signaling Pathway ◽  
Panax Notoginseng ◽  
Neonatal Rat ◽  
Mrna Levels ◽  
Effective Components ◽  
Cultured Cortical Neurons ◽  
Rat Cortical Neurons ◽  
Neuron Growth

Background & Objective: Notoginsenoside R1 (NGR1) is one of the main effective components of Panax notoginseng. Method: Primary cortical neurons were harvested from neonatal rats and cultured to analyze the role of NGR1 in neuronal growth and the effects of NGR1 on the Wnt/β-catenin signaling pathway. Following treatment with NGR1, immunocytochemistry was used to detect expression of Tuj1 and MAP2, and RT-qPCR was used to measure mRNA levels of key factors in the Wnt signaling pathway. Results: Results showed that NGR1 promotes growth of cultured neurons and significantly upregulates mRNA levels of β-catenin, Dishevelled, and Frizzled. To further confirm whether NGR1 promoted cortical neuron growth via the Wnt/β-catenin signaling pathway, we knocked down β- catenin mRNA by siRNA interference; following NGR1 treatment of β-catenin-knockdown neurons, β-catenin mRNA levels increased significantly. Conclusion: In conclusion, these results demonstrate that NGR1 promotes growth of cultured cortical neurons from the neonatal rat, possibly via the Wnt/β-catenin signaling pathway.

Abstract 7: Activation Of Neuronal At 1 R Exacerbates Hypertension-induced Reduction In Neuronal Function.

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Jiaxi Xu ◽  
Eric D Lazartigues
Keyword(s):  
Cortical Neurons ◽  
Mrna Levels ◽  
Ang Ii ◽  
Neuronal Function ◽  
Salt Treatment ◽  
Bdnf Expression ◽  
Neurogenic Hypertension ◽  
Discs Large ◽  
Salt Hypertension ◽  
Cerebrovascular System

Hypertension has now been considered as one of the risk factors of Alzheimer's disease (AD), due to its contribution to the dysfunction of cerebrovascular system. To investigate its neuronal contribution, hypertension was induced in C57BL/6j male mice by either systemic infusion of Ang-II (600 ng/kg/min, s.c., 14 days) or DOCA-salt treatment (1 mg/g, s.c., 21 days), then markers for neuronal function were measured via qRT-PCR. In the hippocampus, Ang-II treatment significantly down-regulated the mRNA levels of BDNF (brain-derived neurotrophic factor) and DLG4 (discs large homolog 4, encoding PSD95), while DOCA-salt treatment only down-regulated BDNF expression (P<0.05 vs. sham, n=6). Notably, the expression of PI4KIIIβ, a key kinase for phosphatidylinositol-4,5-isphosphate (PIP 2 ) re-synthesis, was found to be markedly down-regulated in the hippocampus of both hypertension models (P<0.05 vs. sham, n=6). PI4K activity has been closely associated with the progression of neurodegenerative disorders, especially AD, therefore suggesting that reduction of neuronal function could be a part of the etiology of hypertension-related cognitive decline. We have demonstrated that neuronal AT 1 R plays pivotal role in the maintenance of neurogenic hypertension, and here we hypothesized that activation of AT 1 R could also exacerbate hypertension-induced reduction in neuronal function. In mice with DOCA-salt hypertension, the function of cortical neurons was shown to be improved by selective deletion of neuronal AT 1a R, as evidenced by significantly higher mRNA levels of BDNF and PI4KIIIβ, compared to the controls (P<0.05 vs. sham, n=6). To further study the possible involvement of neuronal AT 1 R in AD, 5хFAD mice were bred with mice with neuronal AT 1 R deletion (AT1NKO). AD-associated reduction of ACE2 protein, mainly in neurons, was found to be slightly ameliorated in the prefrontal cortex of 5хFAD-AT1NKO, compared to the age/sex-matched 5хFAD, showing by immunocytochemistry (24610 ±4182 vs. 13420 ±3720 AFU, n=6 slices). Although the detailed mechanism is still unknown, our data suggest that, neuron-expressing AT 1 R could participate in the development of hypertension-associated cognitive impairment and AD, independently of vascular AT 1 R.

scholarly journals Influenza Virus Induces Inflammatory Response in Mouse Primary Cortical Neurons with Limited Viral Replication

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Gefei Wang ◽  
Rui Li ◽  
Zhiwu Jiang ◽  
Liming Gu ◽  
Yanxia Chen ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Inflammatory Response ◽  
Viral Replication ◽  
Cortical Neurons ◽  
Influenza A ◽  
Type I Interferons ◽  
Type I ◽  
Mrna Levels ◽  
Influenza A Viruses ◽  
Primary Cortical Neurons

Unlike stereotypical neurotropic viruses, influenza A viruses have been detected in the brain tissues of human and animal models. To investigate the interaction between neurons and influenza A viruses, mouse cortical neurons were isolated, infected with human H1N1 influenza virus, and then examined for the production of various inflammatory molecules involved in immune response. We found that replication of the influenza virus in neurons was limited, although early viral transcription was not affected. Virus-induced neuron viability decreased at 6 h postinfection (p.i.) but increased at 24 h p.i. depending upon the viral strain. Virus-induced apoptosis and cytopathy in primary cortical neurons were not apparent at 24 h p.i. The mRNA levels of inflammatory cytokines, chemokines, and type I interferons were upregulated at 6 h and 24 h p.i. These results indicate that the influenza virus induces inflammatory response in mouse primary cortical neurons with limited viral replication. The cytokines released in viral infection-induced neuroinflammation might play critical roles in influenza encephalopathy, rather than in viral replication-induced cytopathy.

Cerebellar volume mediates the relationship between FMR1 mRNA levels and voluntary step initiation in males with the premutation

2017 ◽  
Vol 50 ◽  
pp. 5-12 ◽  
Author(s):  
Darren R. Hocking ◽  
Rachael C. Birch ◽  
Quang M. Bui ◽  
Jasmine C. Menant ◽  
Stephen R. Lord ◽  
...  
Keyword(s):  
Mrna Levels ◽  
Cerebellar Volume ◽  
Step Initiation ◽  
Fmr1 Mrna ◽  
The Relationship

scholarly journals Inhibition of DNA Methyltransferases Blocks Mutant Huntingtin-Induced Neurotoxicity

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Yanchun Pan ◽  
Takuji Daito ◽  
Yo Sasaki ◽  
Yong Hee Chung ◽  
Xiaoyun Xing ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cortical Neurons ◽  
Transcriptional Repression ◽  
Cytosine Methylation ◽  
Critical Role ◽  
Dna Methyltransferases ◽  
Mrna Levels ◽  
Mutant Huntingtin ◽  
Striatal Neurons

Abstract Although epigenetic abnormalities have been described in Huntington’s disease (HD), the causal epigenetic mechanisms driving neurodegeneration in HD cortex and striatum remain undefined. Using an epigenetic pathway-targeted drug screen, we report that inhibitors of DNA methyltransferases (DNMTs), decitabine and FdCyd, block mutant huntingtin (Htt)-induced toxicity in primary cortical and striatal neurons. In addition, knockdown of DNMT3A or DNMT1 protected neurons against mutant Htt-induced toxicity, together demonstrating a requirement for DNMTs in mutant Htt-triggered neuronal death and suggesting a neurodegenerative mechanism based on DNA methylation-mediated transcriptional repression. Inhibition of DNMTs in HD model primary cortical or striatal neurons restored the expression of several key genes, including Bdnf, an important neurotrophic factor implicated in HD. Accordingly, the Bdnf promoter exhibited aberrant cytosine methylation in mutant Htt-expressing cortical neurons. In vivo, pharmacological inhibition of DNMTs in HD mouse brains restored the mRNA levels of key striatal genes known to be downregulated in HD. Thus, disturbances in DNA methylation play a critical role in mutant Htt-induced neuronal dysfunction and death, raising the possibility that epigenetic strategies targeting abnormal DNA methylation may have therapeutic utility in HD.

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