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Is dopamine transporter-mediated dopaminergic signaling in the retina a noninvasive biomarker for attention-deficit/ hyperactivity disorder? A study in a novel dopamine transporter variant Val559 transgenic mouse model.
Dai H, Jackson CR, Davis GL, Blakely RD, McMahon DG
(2017) J Neurodev Disord 9: 38
MeSH Terms: Animals, Attention Deficit Disorder with Hyperactivity, Biomarkers, Disease Models, Animal, Dopamine, Dopamine Plasma Membrane Transport Proteins, Electroretinography, Female, Male, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Transgenic, Retina, Vision, Ocular
Show Abstract · Added February 9, 2018
BACKGROUND - Dopamine (DA) is a critical neuromodulator in the retina. Disruption of retinal DA synthesis and signaling significantly attenuates light-adapted, electroretinogram (ERG) responses, as well as contrast sensitivity and acuity. As these measures can be detected noninvasively, they may provide opportunities to detect disease processes linked to perturbed DA signaling. Recently, we identified a rare, functional DA transporter (DAT, SLC6A3) coding substitution, Ala559Val, in subjects with attention-deficit/hyperactivity disorder (ADHD), demonstrating that DAT Val559 imparts anomalous DA efflux (ADE) with attendant physiological, pharmacological, and behavioral phenotypes. To understand the broader impact of ADE on ADHD, noninvasive measures sensitive to DAT reversal are needed.
METHODS - Here, we explored this question through ERG-based analysis of retinal light responses, as well as HPLC measurements of retinal DA in DAT Val559 mice.
RESULTS - Male mice homozygous (HOM) for the DAT Val559 variant demonstrated increased, light-adapted ERG b-wave amplitudes compared to wild type (WT) and heterozygous (HET) mice, whereas dark-adapted responses were indistinguishable across genotypes. The elevated amplitude of the photopic light responses in HOM mice could be mimicked in WT mice by applying D and D DA receptor agonists and suppressed in HOM mice by introducing D antagonist, supporting elevated retinal DA signaling arising from ADE. Following the challenge with amphetamine, WT exhibited an increase in light-adapted response amplitudes, while HOM did not. Total retinal DA content was similar across genotypes. Interestingly, female DAT Val559 HOM animals revealed no significant difference in photopic ERG responses when compared with WT and HET littermates.
CONCLUSIONS - These data reveal that noninvasive, in vivo evaluation of retinal responses to light can reveal physiological signatures of ADE, suggesting a possible approach to the segregation of neurobehavioral disorders based on the DAT-dependent control of DA signaling.
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14 MeSH Terms
Interleukin-22 drives nitric oxide-dependent DNA damage and dysplasia in a murine model of colitis-associated cancer.
Wang C, Gong G, Sheh A, Muthupalani S, Bryant EM, Puglisi DA, Holcombe H, Conaway EA, Parry NAP, Bakthavatchalu V, Short SP, Williams CS, Wogan GN, Tannenbaum SR, Fox JG, Horwitz BH
(2017) Mucosal Immunol 10: 1504-1517
MeSH Terms: Animals, Antibodies, Blocking, Colitis, Ulcerative, Colon, Colonic Neoplasms, DNA Breaks, Double-Stranded, DNA-Binding Proteins, Disease Models, Animal, Helicobacter Infections, Helicobacter hepaticus, Humans, Inflammation, Interleukins, Macrophages, Peritoneal, Mice, Mice, 129 Strain, Mice, Knockout, Neoplasms, Nitric Oxide, Nitric Oxide Synthase Type II
Show Abstract · Added April 15, 2019
The risk of colon cancer is increased in patients with Crohn's disease and ulcerative colitis. Inflammation-induced DNA damage could be an important link between inflammation and cancer, although the pathways that link inflammation and DNA damage are incompletely defined. RAG2-deficient mice infected with Helicobacter hepaticus (Hh) develop colitis that progresses to lower bowel cancer. This process depends on nitric oxide (NO), a molecule with known mutagenic potential. We have previously hypothesized that production of NO by macrophages could be essential for Hh-driven carcinogenesis, however, whether Hh infection induces DNA damage in this model and whether this depends on NO has not been determined. Here we demonstrate that Hh infection of RAG2-deficient mice rapidly induces expression of iNOS and the development of DNA double-stranded breaks (DSBs) specifically in proliferating crypt epithelial cells. Generation of DSBs depended on iNOS activity, and further, induction of iNOS, the generation of DSBs, and the subsequent development of dysplasia were inhibited by depletion of the Hh-induced cytokine IL-22. These results demonstrate a strong association between Hh-induced DNA damage and the development of dysplasia, and further suggest that IL-22-dependent induction of iNOS within crypt epithelial cells rather than macrophages is a driving force in this process.
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Effects of deletion on body weight and cholesterol in mice.
Boortz KA, Syring KE, Pound LD, Mo H, Bastarache L, Oeser JK, McGuinness OP, Denny JC, O'Brien RM
(2017) J Mol Endocrinol 58: 127-139
MeSH Terms: Animals, Blood Glucose, Body Weight, Cholesterol, Diet, High-Fat, Fasting, Female, Gene Deletion, Gene Expression, Genetic Association Studies, Genetic Background, Glucose Tolerance Test, Glucose-6-Phosphatase, Insulin, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Pancreas, Polymorphism, Single Nucleotide
Show Abstract · Added March 14, 2018
Genome-wide association study (GWAS) data have linked the gene to variations in fasting blood glucose (FBG). encodes an islet-specific glucose-6-phosphatase catalytic subunit that forms a substrate cycle with the beta cell glucose sensor glucokinase. This cycle modulates the glucose sensitivity of insulin secretion and hence FBG. GWAS data have not linked to variations in body weight but we previously reported that female C57BL/6J -knockout (KO) mice were lighter than wild-type littermates on both a chow and high-fat diet. The purpose of this study was to compare the effects of deletion on FBG and body weight in both chow-fed and high-fat-fed mice on two other genetic backgrounds. FBG was reduced in KO mice largely independent of gender, genetic background or diet. In contrast, the effect of deletion on body weight was markedly influenced by these variables. Deletion of conferred a marked protection against diet-induced obesity in male mixed genetic background mice, whereas in 129SvEv mice deletion of had no effect on body weight. deletion also reduced plasma cholesterol levels in a manner dependent on gender, genetic background and diet. An association between and plasma cholesterol was also observed in humans through electronic health record-derived phenotype analyses. These observations suggest that the action of G6PC2 on FBG is largely independent of the influences of environment, modifier genes or epigenetic events, whereas the action of G6PC2 on body weight and cholesterol are influenced by unknown variables.
© 2017 Society for Endocrinology.
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21 MeSH Terms
IL-4/IL-13-mediated polarization of renal macrophages/dendritic cells to an M2a phenotype is essential for recovery from acute kidney injury.
Zhang MZ, Wang X, Wang Y, Niu A, Wang S, Zou C, Harris RC
(2017) Kidney Int 91: 375-386
MeSH Terms: Acute Kidney Injury, Animals, Cell Plasticity, Dendritic Cells, Diphtheria Toxin, Disease Models, Animal, Fibrosis, Genotype, Heparin-binding EGF-like Growth Factor, Interleukin-13, Interleukin-4, Janus Kinase 3, Kidney, Macrophages, Male, Mice, 129 Strain, Mice, Inbred BALB C, Mice, Knockout, Phenotype, Recovery of Function, Reperfusion Injury, STAT6 Transcription Factor, Signal Transduction, Time Factors
Show Abstract · Added April 26, 2017
Cytokines IL-4 and IL-13 play important roles in polarization of macrophages/dendritic cells to an M2 phenotype, which is important for recovery from acute kidney injury. Both IL-4 and IL-13 activate JAK3/STAT6 signaling. In mice with diphtheria toxin receptor expression in proximal tubules (selective injury model), a relatively selective JAK3 inhibitor, tofacitinib, led to more severe kidney injury, delayed recovery from acute kidney injury, increased inflammatory M1 phenotype markers and decreased reparative M2 phenotype markers of macrophages/dendritic cells, and development of more severe renal fibrosis after diphtheria toxin administration. Similarly, there was delayed recovery and increased tubulointerstitial fibrosis in these diphtheria toxin-treated mice following tamoxifen-induced deletion of both IL-4 and IL-13, with increased levels of M1 and decreased levels of M2 markers in the macrophages/dendritic cells. Furthermore, deletion of IL-4 and IL-13 led to a decrease of tissue reparative M2a phenotype markers but had no effect on anti-inflammatory M2c phenotype markers. Deletion of IL-4 and IL-13 also inhibited recovery from ischemia-reperfusion injury in association with increased M1 and decreased M2 markers and promoted subsequent tubulointerstitial fibrosis. Thus, IL-4 and IL-13 are required to effectively polarize macrophages/dendritic cells to an M2a phenotype and to promote recovery from acute kidney injury.
Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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24 MeSH Terms
Prefrontal Cortex-Mediated Impairments in a Genetic Model of NMDA Receptor Hypofunction Are Reversed by the Novel M PAM VU6004256.
Grannan MD, Mielnik CA, Moran SP, Gould RW, Ball J, Lu Z, Bubser M, Ramsey AJ, Abe M, Cho HP, Nance KD, Blobaum AL, Niswender CM, Conn PJ, Lindsley CW, Jones CK
(2016) ACS Chem Neurosci 7: 1706-1716
MeSH Terms: Action Potentials, Animals, Cholinergic Agents, Cognition Disorders, Conditioning (Psychology), Disease Models, Animal, Drug Evaluation, Preclinical, Fear, Gene Knockdown Techniques, Heterocyclic Compounds, 4 or More Rings, Long-Term Synaptic Depression, Male, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Nerve Tissue Proteins, Nootropic Agents, Prefrontal Cortex, Pyramidal Cells, Receptors, N-Methyl-D-Aspartate, Recognition (Psychology), Tissue Culture Techniques
Show Abstract · Added April 6, 2017
Abnormalities in the signaling of the N-methyl-d-aspartate subtype of the glutamate receptor (NMDAR) within cortical and limbic brain regions are thought to underlie many of the complex cognitive and affective symptoms observed in individuals with schizophrenia. The M muscarinic acetylcholine receptor (mAChR) subtype is a closely coupled signaling partner of the NMDAR. Accumulating evidence suggests that development of selective positive allosteric modulators (PAMs) of the M receptor represent an important treatment strategy for the potential normalization of disruptions in NMDAR signaling in patients with schizophrenia. In the present studies, we evaluated the effects of the novel and highly potent M PAM, VU6004256, in ameliorating selective prefrontal cortical (PFC)-mediated physiologic and cognitive abnormalities in a genetic mouse model of global reduction in the NR1 subunit of the NMDAR (NR1 knockdown [KD]). Using slice-based extracellular field potential recordings, deficits in muscarinic agonist-induced long-term depression (LTD) in layer V of the PFC in the NR1 KD mice were normalized with bath application of VU6004256. Systemic administration of VU6004256 also reduced excessive pyramidal neuron firing in layer V PFC neurons in awake, freely moving NR1 KD mice. Moreover, selective potentiation of M by VU6004256 reversed the performance impairments of NR1 KD mice observed in two preclinical models of PFC-mediated learning, specifically the novel object recognition and cue-mediated fear conditioning tasks. VU6004256 also produced a robust, dose-dependent reduction in the hyperlocomotor activity of NR1 KD mice. Taken together, the current findings provide further support for M PAMs as a novel therapeutic approach for the PFC-mediated impairments in schizophrenia.
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23 MeSH Terms
BMP Antagonist Gremlin 2 Limits Inflammation After Myocardial Infarction.
Sanders LN, Schoenhard JA, Saleh MA, Mukherjee A, Ryzhov S, McMaster WG, Nolan K, Gumina RJ, Thompson TB, Magnuson MA, Harrison DG, Hatzopoulos AK
(2016) Circ Res 119: 434-49
MeSH Terms: Animals, Bone Morphogenetic Protein 2, Cells, Cultured, Endothelial Cells, Female, Humans, Inflammation, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Myocardial Infarction, Myocytes, Cardiac, Proteins, Pyrazoles, Quinolines
Show Abstract · Added July 5, 2016
RATIONALE - We have recently shown that the bone morphogenetic protein (BMP) antagonist Gremlin 2 (Grem2) is required for early cardiac development and cardiomyocyte differentiation. Our initial studies discovered that Grem2 is strongly induced in the adult heart after experimental myocardial infarction (MI). However, the function of Grem2 and BMP-signaling inhibitors after cardiac injury is currently unknown.
OBJECTIVE - To investigate the role of Grem2 during cardiac repair and assess its potential to improve ventricular function after injury.
METHODS AND RESULTS - Our data show that Grem2 is transiently induced after MI in peri-infarct area cardiomyocytes during the inflammatory phase of cardiac tissue repair. By engineering loss- (Grem2(-/-)) and gain- (TG(Grem2)) of-Grem2-function mice, we discovered that Grem2 controls the magnitude of the inflammatory response and limits infiltration of inflammatory cells in peri-infarct ventricular tissue, improving cardiac function. Excessive inflammation in Grem2(-/-) mice after MI was because of overactivation of canonical BMP signaling, as proven by the rescue of the inflammatory phenotype through administration of the canonical BMP inhibitor, DMH1. Furthermore, intraperitoneal administration of Grem2 protein in wild-type mice was sufficient to reduce inflammation after MI. Cellular analyses showed that BMP2 acts with TNFα to induce expression of proinflammatory proteins in endothelial cells and promote adhesion of leukocytes, whereas Grem2 specifically inhibits the BMP2 effect.
CONCLUSIONS - Our results indicate that Grem2 provides a molecular barrier that controls the magnitude and extent of inflammatory cell infiltration by suppressing canonical BMP signaling, thereby providing a novel mechanism for limiting the adverse effects of excessive inflammation after MI.
© 2016 American Heart Association, Inc.
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18 MeSH Terms
Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function.
Margolis KG, Li Z, Stevanovic K, Saurman V, Israelyan N, Anderson GM, Snyder I, Veenstra-VanderWeele J, Blakely RD, Gershon MD
(2016) J Clin Invest 126: 2221-35
MeSH Terms: Animals, Autism Spectrum Disorder, Enteric Nervous System, Female, Gastrointestinal Motility, Gastrointestinal Tract, Genetic Variation, Humans, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Mice, Mutant Strains, Models, Animal, Neurogenesis, Pregnancy, Serotonin, Serotonin Plasma Membrane Transport Proteins
Show Abstract · Added August 31, 2018
Autism spectrum disorder (ASD) is an increasingly common behavioral condition that frequently presents with gastrointestinal (GI) disturbances. It is not clear, however, how gut dysfunction relates to core ASD features. Multiple, rare hyperfunctional coding variants of the serotonin (5-HT) transporter (SERT, encoded by SLC6A4) have been identified in ASD. Expression of the most common SERT variant (Ala56) in mice increases 5-HT clearance and causes ASD-like behaviors. Here, we demonstrated that Ala56-expressing mice display GI defects that resemble those seen in mice lacking neuronal 5-HT. These defects included enteric nervous system hypoplasia, slow GI transit, diminished peristaltic reflex activity, and proliferation of crypt epithelial cells. An opposite phenotype was seen in SERT-deficient mice and in progeny of WT dams given the SERT antagonist fluoxetine. The reciprocal phenotypes that resulted from increased or decreased SERT activity support the idea that 5-HT signaling regulates enteric neuronal development and can, when disturbed, cause long-lasting abnormalities of GI function. Administration of a 5-HT4 agonist to Ala56 mice during development prevented Ala56-associated GI perturbations, suggesting that excessive SERT activity leads to inadequate 5-HT4-mediated neurogenesis. We propose that deficient 5-HT signaling during development may contribute to GI and behavioral features of ASD. The consequences of therapies targeting SERT during pregnancy warrant further evaluation.
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Lipoxin Inhibits Fungal Uptake by Macrophages and Reduces the Severity of Acute Pulmonary Infection Caused by Paracoccidioides brasiliensis.
Ribeiro LR, Loures FV, de Araújo EF, Feriotti C, Costa TA, Serezani CH, Jancar S, Calich VL
(2015) Mediators Inflamm 2015: 852574
MeSH Terms: Acetates, Animals, Arachidonate 5-Lipoxygenase, Dinoprostone, Inflammation Mediators, Leukotriene Antagonists, Leukotriene C4, Lipoxins, Macrophages, Alveolar, Male, Mice, Mice, 129 Strain, Mice, Inbred A, Mice, Knockout, Paracoccidioides, Paracoccidioidomycosis, Quinolines, Receptors, Leukotriene, Receptors, Pattern Recognition
Show Abstract · Added May 4, 2017
Cysteinyl leukotrienes (CysLTs) and lipoxins (LXs) are lipid mediators that control inflammation, with the former inducing and the latter inhibiting this process. Because the role played by these mediators in paracoccidioidomycosis was not investigated, we aimed to characterize the role of CysLT in the pulmonary infection developed by resistant (A/J) and susceptible (B10.A) mice. 48 h after infection, elevated levels of pulmonary LTC4 and LXA4 were produced by both mouse strains, but higher levels were found in the lungs of susceptible mice. Blocking the CysLTs receptor by MTL reduced fungal loads in B10.A, but not in A/J mice. In susceptible mice, MLT treatment led to reduced influx of PMN leukocytes, increased recruitment of monocytes, predominant synthesis of anti-inflammatory cytokines, and augmented expression of 5- and 15-lipoxygenase mRNA, suggesting a prevalent LXA4 activity. In agreement, MTL-treated macrophages showed reduced fungal burdens associated with decreased ingestion of fungal cells. Furthermore, the addition of exogenous LX reduced, and the specific blockade of the LX receptor increased the fungal loads of B10.A macrophages. This study showed for the first time that inhibition of CysLTs signaling results in less severe pulmonary paracoccidioidomycosis that occurs in parallel with elevated LX activity and reduced infection of macrophages.
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19 MeSH Terms
Ethanol produces corticotropin-releasing factor receptor-dependent enhancement of spontaneous glutamatergic transmission in the mouse central amygdala.
Silberman Y, Fetterly TL, Awad EK, Milano EJ, Usdin TB, Winder DG
(2015) Alcohol Clin Exp Res 39: 2154-62
MeSH Terms: Animals, Central Amygdaloid Nucleus, Dose-Response Relationship, Drug, Ethanol, Excitatory Postsynaptic Potentials, Glutamic Acid, Humans, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Transgenic, Organ Culture Techniques, Receptors, Corticotropin-Releasing Hormone, Synaptic Transmission
Show Abstract · Added March 26, 2019
BACKGROUND - Ethanol (EtOH) modulation of central amygdala (CeA) neurocircuitry plays a key role in the development of alcoholism via activation of the corticotropin-releasing factor (CRF) receptor (CRFR) system. Previous work has predominantly focused on EtOH × CRF interactions on the CeA GABA circuitry; however, our laboratory recently showed that CRF enhances CeA glutamatergic transmission. Therefore, this study sought to determine whether EtOH modulates CeA glutamate transmission via activation of CRF signaling.
METHODS - The effects of EtOH on spontaneous excitatory postsynaptic currents (sEPSCs) and basal resting membrane potentials were examined via standard electrophysiology methods in adult male C57BL/6J mice. Local ablation of CeA CRF neurons (CRF(CeAhDTR) ) was achieved by targeting the human diphtheria toxin receptor (hDTR) to CeA CRF neurons with an adeno-associated virus. Ablation was quantified post hoc with confocal microscopy. Genetic targeting of the diphtheria toxin active subunit to CRF neurons (CRF(DTA) mice) ablated CRF neurons throughout the central nervous system, as assessed by quantitative reverse transcriptase polymerase chain reaction quantification of CRF mRNA.
RESULTS - Acute bath application of EtOH significantly increased sEPSC frequency in a concentration-dependent manner in CeA neurons, and this effect was blocked by pretreatment of co-applied CRFR1 and CRFR2 antagonists. In experiments utilizing a CRF-tomato reporter mouse, EtOH did not significantly alter the basal membrane potential of CeA CRF neurons. The ability of EtOH to enhance CeA sEPSC frequency was not altered in CRF(CeAhDTR) mice despite a ~78% reduction in CeA CRF cell counts. The ability of EtOH to enhance CeA sEPSC frequency was also not altered in the CRF(DTA) mice despite a 3-fold reduction in CRF mRNA levels.
CONCLUSIONS - These findings demonstrate that EtOH enhances spontaneous glutamatergic transmission in the CeA via a CRFR-dependent mechanism. Surprisingly, our data suggest that this action may not require endogenous CRF.
Copyright © 2015 by the Research Society on Alcoholism.
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Loss of hepatocyte ERBB3 but not EGFR impairs hepatocarcinogenesis.
Scheving LA, Zhang X, Stevenson MC, Weintraub MA, Abbasi A, Clarke AM, Threadgill DW, Russell WE
(2015) Am J Physiol Gastrointest Liver Physiol 309: G942-54
MeSH Terms: Age Factors, Animals, Cell Proliferation, Cell Transformation, Neoplastic, Diethylnitrosamine, ErbB Receptors, Genotype, Hepatocytes, Liver Neoplasms, Liver Regeneration, Male, Mice, 129 Strain, Mice, Inbred C3H, Mice, Knockout, Phenotype, Phosphorylation, Receptor, ErbB-3, STAT3 Transcription Factor, Signal Transduction
Show Abstract · Added May 5, 2016
Epidermal growth factor receptor (EGFR) and ERBB3 have been implicated in hepatocellular carcinogenesis (HCC). However, it is not known whether altering the activity of either EGFR or ERBB3 affects HCC development. We now show that Egfr(Dsk5) mutant mice, which have a gain-of-function allele that increases basal EGFR kinase activity, develop spontaneous HCC by 10 mo of age. Their tumors show increased activation of EGFR, ERBB2, and ERBB3 as well as AKT and ERK1,2. Hepatocyte-specific models of EGFR and ERBB3 gene ablation were generated to evaluate how the loss of these genes affected tumor progression. Loss of either receptor tyrosine kinase did not alter liver development or regenerative liver growth following carbon tetrachloride injection. However, using a well-characterized model of HCC in which N-nitrosodiethylamine is injected into 14-day-old mice, we discovered that loss of hepatocellular ERBB3 but not EGFR, which occurred after tumor initiation, retarded liver tumor formation and cell proliferation. We found no evidence that this was due to increased apoptosis or diminished phosphatidylinositol-3-kinase activity in the ERBB3-null cells. However, the relative amount of phospho-STAT3 was diminished in tumors derived from these mice, suggesting that ERBB3 may promote HCC through STAT3 activation.
Copyright © 2015 the American Physiological Society.
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19 MeSH Terms