scholarly journals MeCP2 in cholinergic interneurons of nucleus accumbens regulates fear learning

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Ying Zhang ◽  
Yi Zhu ◽  
Shu-Xia Cao ◽  
Peng Sun ◽  
Jian-Ming Yang ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Gabaa Receptors ◽  
Molecular Mechanisms ◽  
Transcriptional Regulator ◽  
Fear Learning ◽  
Abnormal Behavior ◽  
Mecp2 Gene ◽  
Cholinergic Interneurons ◽  
Deficient Mice

Methyl-CpG-binding protein 2 (MeCP2) encoded by the MECP2 gene is a transcriptional regulator whose mutations cause Rett syndrome (RTT). Mecp2-deficient mice show fear regulation impairment; however, the cellular and molecular mechanisms underlying this abnormal behavior are largely uncharacterized. Here, we showed that Mecp2 gene deficiency in cholinergic interneurons of the nucleus accumbens (NAc) dramatically impaired fear learning. We further found that spontaneous activity of cholinergic interneurons in Mecp2-deficient mice decreased, mediated by enhanced inhibitory transmission via α2-containing GABAA receptors. With MeCP2 restoration, opto- and chemo-genetic activation, and RNA interference in ChAT-expressing interneurons of the NAc, impaired fear retrieval was rescued. Taken together, these results reveal a previously unknown role of MeCP2 in NAc cholinergic interneurons in fear regulation, suggesting that modulation of neurons in the NAc may ameliorate fear-related disorders.

Pitx3 Deficiency in Mice Affects Cholinergic Modulation of GABAergic Synapses in the Nucleus Accumbens

2006 ◽  
Vol 96 (4) ◽  
pp. 2034-2041 ◽  
Author(s):  
Mischa de Rover ◽  
Johannes C. Lodder ◽  
Marten P. Smidt ◽  
Arjen B. Brussaard
Keyword(s):  
Nucleus Accumbens ◽  
Medium Spiny Neurons ◽  
Wild Type ◽  
Cholinergic Modulation ◽  
Firing Patterns ◽  
Neural Adaptations ◽  
Cholinergic Interneurons ◽  
Spiny Neurons ◽  
Gating Mechanism ◽  
Deficient Mice

We investigated to what extent Pitx3 deficiency, causing hyperdopaminergic transmission in the nucleus accumbens microcircuitry, may lead to developmental changes. First, spontaneous firing activity of cholinergic interneurons in the nucleus accumbens was recorded in vitro. Firing patterns in the Pitx3-deficient mice were more variable and intrinsically different from those observed in wild-type mice. Next, to test whether the irregular firing patterns observed in mutant mice affected the endogenous nicotinic modulation of the GABAergic input of medium spiny neurons, we recorded spontaneous GABAergic inputs to these cells before and after the application of the nicotinic receptor blocker mecamylamine. Effects of mecamylamine were found in slices of either genotype, but in a rather inconsistent manner. Possibly this was attributable to heterogeneity in firing of nearby cholinergic interneurons. Thus paired recordings of cholinergic interneurons and medium spiny neurons were performed to more precisely control the experimental conditions of the cholinergic modulation of GABAergic synaptic transmission. We found that controlling action potential firing in cholinergic neurons leads to a conditional increase in GABAergic input frequency in wild-type mice but not in Pitx3-deficient mice. We conclude that Pitx3-deficient mice have neural adaptations at the level of the nucleus accumbens microcircuitry that in turn may have behavioral consequences. It is discussed to what extent dopamine release in the nucleus accumbens may be a long-term gating mechanism leading to alterations in cholinergic transmission in the nucleus accumbens, in line with previously reported neural adaptations found as consequences of repeated drug treatment in rodents.

scholarly journals A comprehensive protein–protein interactome for yeast PAS kinase 1 reveals direct inhibition of respiration through the phosphorylation of Cbf1

2014 ◽  
Vol 25 (14) ◽  
pp. 2199-2215 ◽  
Author(s):  
Desiree DeMille ◽  
Benjamin T. Bikman ◽  
Andrew D. Mathis ◽  
John T. Prince ◽  
Jordan T. Mackay ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Protein Modification ◽  
Molecular Mechanisms ◽  
Binding Partners ◽  
Pas Kinase ◽  
Protein Interactome ◽  
Deficient Mice

Per-Arnt-Sim (PAS) kinase is a sensory protein kinase required for glucose homeostasis in yeast, mice, and humans, yet little is known about the molecular mechanisms of its function. Using both yeast two-hybrid and copurification approaches, we identified the protein–protein interactome for yeast PAS kinase 1 (Psk1), revealing 93 novel putative protein binding partners. Several of the Psk1 binding partners expand the role of PAS kinase in glucose homeostasis, including new pathways involved in mitochondrial metabolism. In addition, the interactome suggests novel roles for PAS kinase in cell growth (gene/protein expression, replication/cell division, and protein modification and degradation), vacuole function, and stress tolerance. In vitro kinase studies using a subset of 25 of these binding partners identified Mot3, Zds1, Utr1, and Cbf1 as substrates. Further evidence is provided for the in vivo phosphorylation of Cbf1 at T211/T212 and for the subsequent inhibition of respiration. This respiratory role of PAS kinase is consistent with the reported hypermetabolism of PAS kinase–deficient mice, identifying a possible molecular mechanism and solidifying the evolutionary importance of PAS kinase in the regulation of glucose homeostasis.

Dendritic cell-derived IL-2 production is regulated by IL-15 in humans and in mice

Blood ◽  
2005 ◽  
Vol 105 (2) ◽  
pp. 697-702 ◽  
Author(s):  
Sonia Feau ◽  
Valeria Facchinetti ◽  
Francesca Granucci ◽  
Stefania Citterio ◽  
David Jarrossay ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Molecular Mechanisms ◽  
Interleukin 2 ◽  
Adaptive Immune ◽  
Deficient Mice ◽  
Mouse System

Abstract Dendritic cells (DCs) are involved in the initiation and regulation of innate and adaptive immune responses. Several molecular mechanisms regulate these diverse DC functions, and we have previously reported that mouse dendritic cells (mDCs) can produce interleukin-2 (IL-2) in vitro and in vivo, in response to microbial activation and T-cell-mediated stimuli. This property is shared by different DC subtypes, including Langerhans cells. Here we show that, on appropriate stimulation, human DCs, both plasmacytoid and myeloid subtypes, also express IL-2. Interestingly, the production of IL-2 by myeloid DCs is induced by T-cell-mediated stimuli and depends on the presence of IL-15. The key role of this cytokine in regulating IL-2 production was also confirmed in the mouse system. In particular, we could show that DCs from IL-15-deficient mice were strongly impaired in the ability to produce IL-2 after interactions with different microbial stimuli. Our results indicate that DC-produced IL-2 is tightly coregulated with the expression of IL-15.

Abstract 5290: Cypher Long but not Short Isoform Specific Knockout Mice Result in Cardiac Signaling Defects and Dilated Cardiomyopathy

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Hongqiang Cheng ◽  
Ming Zheng ◽  
Farah Sheikh ◽  
Kunfu Ouyang ◽  
Li Cui ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Knockout Mice ◽  
Molecular Mechanisms ◽  
Heart Function ◽  
Gene Mutations ◽  
Splice Isoforms ◽  
Functional Roles ◽  
Deficient Mice

Our previous studies have demonstrated that Cypher, a PDZ-LIM protein localized at the Z line, plays a pivotal role in heart function. We recently identified long and short splice isoforms of Cypher, which are characterized by the presence and absence of LIM domains, respectively. The LIM domain of Cypher is thought to be involved in signaling, based on its ability to directly interact with signaling proteins. In human patients with dilated cardiomyopathy (DCM) we discovered Cypher gene mutations, which affect either long or short isoform or both isoforms. However, the precise molecular mechanisms underlying the role of Cypher isoforms in DCM remain unclear. To determine the role of Cypher isoforms in cardiac signaling and disease in vivo , we generated two Cypher isoform specific knockout mice. Selective ablation of Cypher long isoforms in mice resulted in partial neonatal lethality. However, hearts from viable Cypher long isoform deficient mice displayed Z line abnormalities and decreased cardiomyocyte widths, which resulted in a progressive form of DCM, characterized by fibrosis, calcification and lethality. The effects on cardiac function and disease observed in long-isoform specific Cypher knockout mice were preceded by significant decreases in cardiac protein kinase C and extracellular signal-regulated kinase signaling. These results are in contrast to Cypher short isoform deficient mice, which were viable with no overt cardiac morphology and signaling abnormalities. These results reveal distinct functional roles for Cypher isoforms in the heart as well as shed light into the molecular mechanisms underlying dilated cardiomyopathy.

Role of GABAA receptors in the endomorphin-1-, but not endomorphin-2-, induced dopamine efflux in the nucleus accumbens of freely moving rats

2008 ◽  
Vol 580 (1-2) ◽  
pp. 87-94 ◽  
Author(s):  
Yuri Aono ◽  
Tadashi Saigusa ◽  
Naoko Mizoguchi ◽  
Tomoyo Iwakami ◽  
Koji Takada ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Gabaa Receptors ◽  
Freely Moving Rats ◽  
Freely Moving ◽  
Dopamine Efflux

scholarly journals Airway epithelial integrin β4 suppresses allergic inflammation by decreasing CCL17 production

2020 ◽  
Vol 134 (13) ◽  
pp. 1735-1749 ◽  
Author(s):  
Lin Yuan ◽  
Xun Zhang ◽  
Ming Yang ◽  
Xizi Du ◽  
Leyuan Wang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Allergic Inflammation ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Th2 Response ◽  
Integrin Β4 ◽  
Dust Mite ◽  
Asthma Patients ◽  
Deficient Mice

Abstract Airway epithelial cells (AECs) play a key role in asthma susceptibility and severity. Integrin β4 (ITGB4) is a structural adhesion molecule that is down-regulated in the airway epithelium of asthma patients. Although a few studies hint toward the role of ITGB4 in asthmatic inflammation pathogenesis, their specific resultant effects remain unexplored. In the present study, we determined the role of ITGB4 of AECs in the regulation of Th2 response and identified the underpinning molecular mechanisms. We found that ITGB4 deficiency led to exaggerated lung inflammation and AHR with higher production of CCL17 in house dust mite (HDM)-treated mice. ITGB4 regulated CCL17 production in AECs through EGFR, ERK and NF-κB pathways. EFGR-antagonist treatment or the neutralization of CCL17 both inhibited exaggerated pathological marks in HDM-challenged ITGB4-deficient mice. Together, these results demonstrated the involvement of ITGB4 deficiency in the development of Th2 responses of allergic asthma by down-regulation of EGFR and CCL17 pathway in AECs.

scholarly journals Amyloidogenic processing of amyloid β protein precursor (APP) is enhanced in the brains of alcadein α–deficient mice

2020 ◽  
Vol 295 (28) ◽  
pp. 9650-9662 ◽  
Author(s):  
Naoya Gotoh ◽  
Yuhki Saito ◽  
Saori Hata ◽  
Haruka Saito ◽  
Daiki Ojima ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Adaptor Protein ◽  
Type I ◽  
Amyloid Β Protein ◽  
Protein Precursor ◽  
Amyloidogenic Processing ◽  
Β Amyloid ◽  
Deficient Mice

Alzheimer's disease (AD) is a very common neurodegenerative disorder, chiefly caused by increased production of neurotoxic β-amyloid (Aβ) peptide generated from proteolytic cleavage of β-amyloid protein precursor (APP). Except for familial AD arising from mutations in the APP and presenilin (PSEN) genes, the molecular mechanisms regulating the amyloidogenic processing of APP are largely unclear. Alcadein α/calsyntenin1 (ALCα/CLSTN1) is a neuronal type I transmembrane protein that forms a complex with APP, mediated by the neuronal adaptor protein X11-like (X11L or MINT2). Formation of the ALCα–X11L–APP tripartite complex suppresses Aβ generation in vitro, and X11L-deficient mice exhibit enhanced amyloidogenic processing of endogenous APP. However, the role of ALCα in APP metabolism in vivo remains unclear. Here, by generating ALCα-deficient mice and using immunohistochemistry, immunoblotting, and co-immunoprecipitation analyses, we verified the role of ALCα in the suppression of amyloidogenic processing of endogenous APP in vivo. We observed that ALCα deficiency attenuates the association of X11L with APP, significantly enhances amyloidogenic β-site cleavage of APP, especially in endosomes, and increases the generation of endogenous Aβ in the brain. Furthermore, we noted amyloid plaque formation in the brains of human APP-transgenic mice in an ALCα-deficient background. These results unveil a potential role of ALCα in protecting cerebral neurons from Aβ-dependent pathogenicity in AD.

scholarly journals Understanding hyperlipidemia and atherosclerosis: lessons from genetically modified apoe and ldlr mice

2005 ◽  
Vol 43 (5) ◽  
Author(s):  
Kristiaan Wouters ◽  
Ronit Shiri-Sverdlov ◽  
Patrick J. van Gorp ◽  
Marc van Bilsen ◽  
Marten H. Hofker
Keyword(s):  
Mouse Models ◽  
Molecular Mechanisms ◽  
Genetically Modified ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipid Lowering ◽  
Density Lipoprotein Receptor ◽  
Mutant Forms ◽  
Deficient Mice

AbstractHyperlipidemia is the most important risk factor for atherosclerosis, which is the major cause of cardiovascular disease. The etiology of hyperlipidemia and atherosclerosis is complex and governed by multiple interacting genes. However, mutations in two genes have been shown to be directly involved, i.e., the low-density lipoprotein receptor (LDLR) and apolipoprotein E (ApoE). Genetically modified mouse models have been instrumental in elucidating the underlying molecular mechanisms in lipid metabolism. In this review, we focus on the use of two of the most widely used mouse models, ApoE- and LDLR-deficient mice. After almost a decade of applications, it is clear that each model has unique strengths and drawbacks when carrying out studies of the role of additional genes and environmental factors such as nutrition and lipid-lowering drugs. Importantly, we elaborate on mice expressing mutant forms of APOE, including the

scholarly journals Author response: MeCP2 in cholinergic interneurons of nucleus accumbens regulates fear learning

2020 ◽  
Author(s):  
Ying Zhang ◽  
Yi Zhu ◽  
Shu-Xia Cao ◽  
Peng Sun ◽  
Jian-Ming Yang ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Fear Learning ◽  
Author Response ◽  
Cholinergic Interneurons
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