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PubMed2005

Different response of the knockout mice lacking b-series gangliosides against botulinum and tetanus toxins.

We assessed the response in knockout mice lacking the b-series (G(D2), G(D1b), G(T1b) and G(Q1b)) gangliosides against Clostridium botulinum (types A, B and E) and tetani toxins. We found that botulinum toxins were fully toxic, while tetanus toxin was much less toxic in the knockout mice. Combining the present results with our previous finding that tetanus toxin and botulinum types A and B toxins showed essentially no toxic activity in the knockout mice lacking both the a-series and b-series gangliosides (complex gangliosides), we concluded that the b-series gangliosides is the major essential substance for tetanus toxin, while b-series gangliosides may be not the essential substance for botulinum toxins, at the initial step during the intoxication process in mouse.

Animals↗

PubMed1994

Application of knockout mice to the experimental analysis of infections with bacteria and protozoa.

Knockout mice with distinct gene deletions are valuable tools for in vivo analyses of the immune response against infectious agents. Studies of bacterial and protozoal infections have shown that antimicrobial immunity is generally defective in knockout mice. At one extreme, deletion of just one gene may completely compromise resistance, while at the other extreme, redundancy in the immune system allows partial compensation for the deleted part.

Animals↗

PubMed2000

Lack of effect of LY314582 (a group 2 metabotropic glutamate receptor agonist) on phencyclidine-induced locomotor activity in metabotropic glutamate receptor 2 knockout mice.

In metabotropic glutamate receptor 2 (mGlu(2)) knockout mice, the group 2 metabotropic glutamate receptor agonist LY314582 (20 mg/kg, i.p.), a racemate of LY354740, inhibits neither spontaneous nor phencyclidine (PCP)-induced (2.5 mg/kg, s.c.) locomotor activity. Since LY314582 attenuated spontaneous and PCP-induced locomotor activity in wild-type control mice, these data indicate that the effects of LY314582 are mediated via the mGlu(2) receptor and not via the mGlu(3) receptor.

Analysis of Variance↗

PubMed1996

Experimental model for human intestinal microsporidiosis in interferon gamma receptor knockout mice infected by Encephalitozoon intestinalis.

Interferon gamma receptor knockout mice developed a chronic infection when inoculated with spores of Encephalitozoon intestinalis which is a cause of intestinal microsporidiosis in AIDS patients. The infection was evaluated by enumeration of the spores of the parasite shed in the stools, histological examination and follow up over a period of six months. A dose-response was demonstrated since higher numbers of spores were excreted and more infection sites were found in mice which were given an increased quantity of parasites. In infected wild type mice, the number of excreted spores decreased until day 16 post-inoculation, then spores were detected sporadically in low numbers. These data confirmed the role of IFN-gamma in the control of E. intestinalis infection. The infection was not lethal suggesting that other factors are involved in regulation of the parasite infection. This model, with the long survival time of the animals together with the measurable quantity of spores shed in the stools will be useful for testing potential therapeutical agents.

AIDS-Related Opportunistic Infections↗

PubMed2005

Properties of hybridomas generated by spleen cells of IL-4- and IL-13-knockout mice.

Interleukin-4 (IL-4)- and IL-13-knockout mice were immunized with murine recombinant IL-4 or IL-13, and spleen cells were fused with P3X63-Ag8.653 myeloma cells. Selection of the antigen-positive hybridomas was fulfilled in the presence of IL-6 containing thymic stroma cell supernatant (TSS). All of the selected anti- IL-4- and anti-IL-13-specific hybridoma clones (eight and 10, respectively) required the presence of TSS (0.5-2.5%) for their cloning, stable growth in large-scale cultures, and production of monoclonal antibodies (MAbs). Several of the anti-IL-4-specific clones were adapted to growth without TSS. However, the loss of antibody-secreting capacity in the process of adaptation to TSS-free growth was detected. The data demonstrate that cytokine-deficient mice technology can be used for generation of MAbs to autologous cytokines.

Animals↗

PubMed2005

Differential effect of imipenem treatment on wild-type and NK cell-deficient CD8 knockout mice during acute intra-abdominal injury.

CD8 knockout mice depleted of natural killer (NK) cells by treatment with anti-asialoGM1 (CD8KO/alphaAsGM1 mice) are resistant to injury caused by cecal ligation and puncture (CLP). However, CLP-induced injury is complex. Potential sources of injury include bacterial dissemination, cecal ischemia, and translocation of bacterial toxins. We treated wild-type and CD8KO/alphaAsGM1 mice with imipenem after CLP to decrease bacterial dissemination. Additional mice were subjected to cecal ligation without puncture of the cecal wall or cecal ligation and removal of cecal contents. Imipenem treatment decreased bacterial counts by at least two orders of magnitude. However, all wild-type mice, whether treated with saline or imipenem, died by 42 h after CLP and exhibited significant hypothermia, metabolic acidosis, and high plasma cytokine concentrations. Wild-type mice subjected to cecal ligation without puncture also died, despite very low bacterial counts in blood, but wild-type mice subjected to cecal ligation and washout of cecal contents survived. In CD8KO/alphaAsGM1 mice subjected to CLP, imipenem treatment increased survival from 50% to 100%. After cecal ligation without puncture, long-term survival was 80-90% in CD8KO/alphaAsGM1 mice. Hypothermia, metabolic acidosis, and cytokine production were attenuated in CD8KO/alphaAsGM1 mice compared with wild-type controls. These results indicate that bacterial dissemination is not a major source of injury in wild-type mice after CLP, but the presence of gut flora in the cecal lumen is required for induction of systemic inflammation after cecal injury. CD8KO/alphaAsGM1 mice are resistant to the systemic manifestations of cecal injury.

Abdominal Injuries↗

PubMed2000

Pulmonary endothelial and epithelial integrity and neutrophil infiltration after endotoxin in interleukin-1 receptor knockout mice.

Previously we found the structural integrity of the aortic endothelium was maintained after the administration of endotoxin in type 1 interleukin-1 (IL-1) receptor knockout mice. In this study, we investigated further the integrity of pulmonary vascular endothelium, airway epithelial, pulmonary microvasculature, and neutrophil infiltration into the microvasculature and respiratory air spaces. Adult male C57BL/129J wild-type mice and C57BL/129J knockout mice possessing a homozygous deletion of the type 1 IL-1 receptor received the following intraperitoneal injections; 1) Escherichia coli endotoxin (ENDT) (10 mg/kg), 2) ENDT (2 mg/kg given for 4 days), or (3) saline vehicle. Wild-type and knockout control animals receiving saline vehicle showed normal endothelial and epithelial ultrastructure with intact membranes. Pulmonary endothelial cell damage was found only in wild-type mice given a single 10 mg/kg endotoxin dose. Airway epithelial damage was found only in wild-type mice given a repetitive dose of endotoxin (2 mg/kg for 4 days). Neutrophil infiltration increased only in mice given a single dose of endotoxin (10 mg/kg) with the wild-type increasing by 32% and the knockouts by 6% compared with the saline control for that group respectively. Serum IL-6 and nitric oxide (indicators of septic shock severity and lethality) significantly increased only in the mice given 10 mg/kg of endotoxin. The maintenance of pulmonary endothelial and epithelial cell integrity and the decrease of neutrophil infiltration in the IL-1 knockout mice suggest that IL-1 contributes significantly to the severity of endotoxin-induced sepsis.

Animals↗

PubMed2000

Refinement of the ipsilateral retinocollicular projection is disrupted in double endothelial and neuronal nitric oxide synthase gene knockout mice.

Development of retinal connections to the superior colliculus (SC) requires an activity dependent refinement process in which axons gradually become restricted to appropriate retinotopic locations. Nitric oxide has been implicated in this process. We tested this possibility by studying the refinement of the ipsilateral retinocollicular projections (IRP) in normal C57-BL/6 mice and in double knockout mice in which the genes for the edothelial and neuronal isoforms of nitric oxide synthase (e, nNOS) were disrupted. Mice aged between P19 and adulthood were perfused 44-48 h after anterograde injections of WGA-HRP into one eye in order to measure the distribution of the labeled IRP. In normal mice, segregation of the IRP was complete at P21, with the ipsilateral projection restricted to the rostro-medial SC. By contrast, the ipsilateral projection was spread over much more of the SC in double e, nNOS knockouts at P21 with patches of label distributed across the entire medio-lateral axis of the rostral 700 microm. Although the distribution of the ipsilateral projection became more restricted in knockout animals at later ages, it was still more extensive than that of normal mice of the same age at P28 and P42. In the adult, the distribution of axons was similar in both normal and double knockout animals. These results show that refinement of the IRP is delayed when expression of eNOS and nNOS is disrupted, presumably to axons with uncorrelated activity because nitric oxide serves as a repellant molecule during normal development.

Animals↗

PubMed2003

On the physiological importance of endoproteolysis of CAAX proteins: heart-specific RCE1 knockout mice develop a lethal cardiomyopathy.

Proteins terminating with a CAAX motif, such as the Ras proteins and the nuclear lamins, undergo post-translational modification of a C-terminal cysteine with an isoprenyl lipid via a process called protein prenylation. After prenylation, the last three residues of CAAX proteins are clipped off by Rce1, an integral membrane endoprotease of the endoplasmic reticulum. Prenylation is crucial to the function of many CAAX proteins, but the physiologic significance of endoproteolytic processing has remained obscure. To address this issue, we used Cre/loxP recombination techniques to create mice lacking Rce1 in the heart, an organ where Rce1 is expressed at particularly high levels. The hearts from heart-specific Rce1 knockout mice manifested reduced levels of both the Rce1 mRNA and CAAX endoprotease activity, and the hearts manifested an accumulation of CAAX protein substrates. The heart-specific Rce1 knockout mice initially appeared healthy but died starting at 3-5 months of age. By 10 months of age, approximately 70% of the mice had died. Pathological studies revealed that the heart-specific Rce1 knockout mice had a dilated cardiomyopathy. By contrast, liver-specific Rce1 knockout mice appeared healthy, had normal transaminase levels, and had normal liver histology. These studies indicate that the endoproteolytic processing of CAAX proteins is essential for cardiac function but is less important for the liver.

Amino Acid Motifs↗

PubMed2000

Enlarged cholinergic forebrain neurons and improved spatial learning in p75 knockout mice.

The p75 low affinity neurotrophin receptor (p75) can induce apoptosis in various neuronal and glial cell types. Because p75 is expressed in the cholinergic neurons of the basal forebrain, p75 knockout mice may be expected to show an increased number of neurons in this region. Previous studies, however, have produced conflicting results, suggesting that genetic background and choice of control mice are critical. To try to clarify the conflicting results from previous reports, we undertook a further study of the basal forebrain in p75 knockout mice, paying particular attention to the use of genetically valid controls. The genetic backgrounds of p75 knockout and control mice used in this study were identical at 95% of loci. There was a small decrease in the number of cholinergic basal forebrain neurons in p75 knockout mice at four months of age compared with controls. This difference was no longer apparent at 15 months due to a reduction in numbers in control mice between the ages of 4 and 15 months. Cholinergic cell size in the basal forebrain was markedly increased in p75 knockout mice compared with controls. Spatial learning performance was consistently better in p75 knockout mice than in controls, and did not show any deterioration with age. The results indicate that p75 exerts a negative influence on the size of cholinergic forebrain neurons, but little effect on neuronal numbers. The markedly better spatial learning suggests that the function, as well as the size, of cholinergic neurons is negatively modulated by p75.

Aging↗

PubMed1996

Enlarged infarcts in endothelial nitric oxide synthase knockout mice are attenuated by nitro-L-arginine.

Infarct size and vascular hemodynamics were measured 24 h after middle cerebral artery (MCA) occlusion in mice genetically deficient in the endothelial nitric oxide synthase (eNOS) isoform. eNOS mutant mice developed larger infarcts (21%) than the wild-type strain when assessed 24 h after intraluminal filament occlusion. Moreover, regional CBF values recorded in the MCA territory by laser-Doppler flowmetry were more severely reduced after occlusion and were disproportionately reduced during controlled hemorrhagic hypotension in autoregulation experiments. Unlike the situation in wild-type mice, nitro-L-arginine superfusion (1 mM) dilated pial arterioles of eNOS knockout mice in a closed cranial window preparation. As noted previously, eNOS mutant mice were hypertensive. However, infarct size remained increased despite lowering blood pressure to normotensive levels by hydralazine treatment. Systemic administration of nitro-L-arginine decreased infarct size in eNOS mutant mice (24%) but not in the wild-type strain. This finding complements published data showing that nitro-L-arginine increases infarct size in knockout mice expressing the eNOS but not the neuronal NOS isoform (i.e., neuronal NOS knockout mice). We conclude that NO production within endothelium may protect brain tissue, perhaps by hemodynamic mechanisms, whereas neuronal NO overproduction may lead to neurotoxicity.

Animals↗

PubMed1999

Reduction of 5-hydroxytryptamine (5-HT)(1A)-mediated temperature and neuroendocrine responses and 5-HT(1A) binding sites in 5-HT transporter knockout mice.

The aim of the present study was to determine whether alterations in 5-hydroxytryptamine (5-HT)(1A) receptors would be found in knockout mice lacking the serotonin transporter (5-HTT). Hypothermic and neuroendocrine responses to the 5-HT(1A) agonist 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) were used to examine the function of 5-HT(1A) receptors. Initial studies evaluated the dose-response and time course of 8-OH-DPAT-induced hypothermia and hormone secretion in normal CD-1 mice (the background strain of the 5-HTT knockout mice). 8-OH-DPAT dose-dependently produced hypothermic responses that peaked at 20 min postinjection. 8-OH-DPAT-induced hypothermia was blocked by the 5-HT(1A) antagonist WAY-100635. 8-OH-DPAT dose-dependently increased the concentrations of plasma oxytocin, corticotropin, and corticosterone. In the 5-HTT knockout (-/-) mice, the hypothermic response to 8-OH-DPAT (0.1 mg/kg s.c.) was completely abolished. Furthermore, 5-HTT-/- mice had significantly attenuated plasma oxytocin and corticosterone responses to 8-OH-DPAT. No significant changes in the hypothermic or hormonal responses to 8-OH-DPAT were observed in heterozygous (5-HTT+/-) mice. [(3)H]8-OH-DPAT- and [(125)I]MPPI [4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridinyl)-iodobenzamido]ethyl] pip erazine]-binding sites in the hypothalamus and [(125)I]MPPI-binding sites in the dorsal raphe were significantly decreased in 5-HTT-/- mice. The results indicate that lack of the 5-HTT is associated with a functional desensitization of 5-HT(1A) receptor responses to 8-OH-DPAT, which may be a consequence, at least in part, of the decrease in density of 5-HT(1A) receptors in the hypothalamus and dorsal raphe of 5-HTT-/- mice.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1998

The use of knockout mice to understand the role of cytokines in fever.

1. In most instances, data obtained using knockout mice to dissect the role of cytokines in fever are similar to data obtained by other, more traditional experimental techniques. 2. Interleukin (IL)-1beta appears to be critically involved in fever caused by some routes of infection/inflammation (e.g. localized inflammation with turpentine). This cytokine has only a small role in fevers caused by i.p. injection of lipopolysaccharide (LPS). These IL-1beta-induced fevers in knockout mice appear to be via the induction of IL-6, similar to LPS-induced fevers in rats. Interleukin-6 also appears to be critically involved in turpentine-induced fever. 3. The precise role of tumour necrosis factor (TNF) in fever is controversial. Data obtained from knockout mice lacking both TNF receptors do not support a pyrogenic role for TNF in fever either to i.p. injection of LPS, s.c. injection of turpentine or following caecal ligation and puncture. 4. The roles of these cytokines in fevers induced by injection of LPS, IL-1beta, turpentine and caecal ligation and puncture are summarized. The data show the complexity of the febrile response. Depending on the types of inflammatory/infectious stimuli, different cytokines play important roles. Because other cytokines are thought to be involved in fever (e.g. macrophage inflammatory protein, interferons), considerable work is still needed to dissect the precise roles of cytokines in fever.

Animals↗

PubMed1997

Differential toxic effects of methamphetamine (METH) and methylenedioxymethamphetamine (MDMA) in multidrug-resistant (mdr1a) knockout mice.

The toxic effects of methamphetamine (METH) (2.5, 5.0 and 10.0 mg/kg) and methylenedioxymethamphetamine (MDMA) (5.0, 10.0 and 20.0 mg/kg) on dopaminergic systems were assessed in the striatum and of the nucleus accumbens in mdr1a wild-type and knockout mice. METH caused significant dose-dependent decreases of dopamine (DA) and DA transporters (DAT) in the striatum and the nucleus accumbens (NAc) of both wild-type and knockout mice. The lowest doses of METH (2.5 mg/kg) caused only small changes in the wild-type, but marked. decreases in the mdr1a knockout mice. The two higher doses (5 mg/kg and 10 mg/kg) caused similar changes in both strains of mice. In contrast to METH, MDMA caused greater percentage decreases in DAT in the wild-type mice. For example, the lowest dose (5 mg/kg) caused significant decreases in DAT in the NAc of wild-type but not of mdr1a knockout mice. The highest dose (20 mg/kg) caused similar changes in both the strains. These results suggest that METH and MDMA interact differentially with P-glycoproteins. These observations document, for the first time, a role for these proteins in the entry of METH and MDMA into the brain via the blood-brain barrier, with P-glycoprotein possibly facilitating the entry of MDMA but interfering with that of METH into the brain.

Animals↗

PubMed2005

Loss of brain-derived neurotrophic factor gene allele exacerbates brain monoamine deficiencies and increases stress abnormalities of serotonin transporter knockout mice.

To study the neurochemical and behavioral effects of altered brain-derived neurotrophic factor (BDNF) expression on a brain serotonin system with diminished serotonin transport capability, a double-mutant mouse model was developed by interbreeding serotonin transporter (SERT) knockout mice with BDNF heterozygous knockout mice (BDNF +/-), producing SERT -/- x BDNF +/- (sb) mice. Prior evidence implicates serotonin and SERT in anxiety and stress responses. Some studies have shown that BDNF supports serotonergic neuronal development, leading to our hypothesis that reduced BDNF availability during development might exaggerate the consequences of absent SERT function. In the present study, brain serotonin and 5-hydroxyindol acetic acid concentrations in male sb mice were significantly reduced in the hippocampus and hypothalamus compared with wild-type control SB mice, BDNF-deficient Sb mice, and serotonin transporter knockout sB mice. The sb mice had significantly increased anxiety-like behaviors compared with SB, Sb, and sB mice as measured on the elevated plus maze test. These sb mice also had significantly greater increases in plasma adrenocorticotrophic hormone than mice with other genotypes after a stressful stimulus. Analysis of neuronal morphology showed that hypothalamic and hippocampal neurons exhibited 25-30% reductions in dendrites in sb mice compared with SB control mice. These findings support the hypothesis that genetic changes in BDNF expression interact with serotonin and other circuits that modulate anxiety and stress-related behaviors. Thus, this double-mutant mouse model should prove valuable in studying other gene x gene consequences for brain plasticity as well as in evaluating epistatic interactions of BDNF and serotonin transporter gene polymorphisms in neuropsychiatric disorders.

Adrenocorticotropic Hormone↗

PubMed2003

Molecular characterization of postnatal development of testicular steroidogenesis in luteinizing hormone receptor knockout mice.

We recently demonstrated that the sexual development of LH receptor (LHR) knockout mice is normal until birth, but is totally arrested thereafter. To study further the functional defects of LHR knockout mice, the expression of selected Leydig cell-specific genes was studied in (-/-) and control (+/+) mice between birth and adulthood. Testis weights were similar at birth in both types of mice, but after about 3 wk, the (-/-) testes remained significantly lighter, weighing only 18% of (+/+) testes on d 70. Testicular testosterone (T) content on d 1 was also similar in (-/-) and (+/+) testes, but it was 97% reduced by d 70 in the former. Likewise, testicular T production in vitro was similar in neonatal (-/-) and (+/+) testes, but became undetectable in adult (-/-) testes. The mRNA expression of cytochrome P450 side-chain cleavage, 17 alpha-hydroxylase cytochrome P450, 17 beta-hydroxysteroid dehydrogenase type III, 3 beta-hydroxysteroid dehydrogenase I (3 beta HSDI), steroidogenic acute regulatory protein, and relaxin-like factor were similar in newborn (-/-) and (+/+) testes, but became gradually very low/undetectable in (-/-) mice. The only exception was the persistently high expression of 3 beta HSDI in peritubular Leydig precursor and mesenchymal cells of the (-/-) testes at all ages. Immunohistochemistry and Western hybridization studies confirmed the above findings. In conclusion, LH action is not essential for the differentiation and function of mouse fetal Leydig cells, but, with the exception of 3 beta HSDI, the expression of the key genes of endocrine function of adult Leydig cells is dependent on LH signaling.

3-Hydroxysteroid Dehydrogenases↗

PubMed2003

Attenuated defense response and low basal blood pressure in orexin knockout mice.

The perifornical area of the hypothalamus has been known as the center for the defense response, or "fight or flight" response, which is characterized by a concomitant rise in arterial blood pressure (AP), heart rate (HR), and respiratory frequency (Rf). We examined whether orexin, a recently identified hypothalamic neuropeptide, contributes to the defense response and basal cardiovascular regulation using orexin knockout mice. Microinjection of a GABA-A receptor antagonist, bicuculline methiodide (0.1-1 mM in 20 nl), to the perifornical area in urethane-anesthetized wild-type mice elicited dose-dependent increases in AP, HR, and Rf. Although similar changes were observed in orexin knockout mice, intensities were smaller and duration was shorter than those in wild-type mice. Moreover, in an awake and freely moving condition, telemeter-indwelling orexin knockout mice showed diminished cardiovascular and behavioral responses to emotional stress in the resident-intruder test. We also found that basal AP in orexin knockout mice was significantly lower in both anesthetized (117 +/- 8 mmHg in wild type and 92 +/- 3 in knockout) and conscious (125 +/- 6 mmHg in wild type and 109 +/- 2 in knockout) conditions. alpha-Adrenergic blockade with prazosin or ganglion blockade with hexamethonium canceled the difference in basal AP. HR and cardiac contractile parameters by echocardiography did not differ between the two strains of mice. These results indicate lower sympathetic vasoconstrictor tone in knockout mice. The present study suggests that orexin-containing neurons in the perifornical area play a role as one of the efferent pathways of defense response and also operate as a regulator of AP at basal condition by activating sympathetic outflow.

Animals↗

PubMed2004

Enhanced gastric emptying of a liquid gastric load in mice lacking cholecystokinin-B receptor: a study of CCK-A,B, and AB receptor gene knockout mice.

BACKGROUND: Although cholecystokinin (CCK) has been shown to inhibit gastric emptying via CCK-A receptors (CCK-ARs), the role of CCK-B receptors (CCK-BRs) has not been verified. We examined whether gastric emptying of a nonnutrient liquid load was modified in CCK-AR, BR, and ARBR gene knockout mice. METHODS: A liquid gastric load prepared with phenol red was administered via an orogastric tube (0.15 ml/mouse). The animals were killed by decapitation, and gastric emptying was estimated at 10 and 30 min after ingestion. The effects of the sulfated form of CCK-8 (CCK-8S) and of graded doses of atropine were examined. In addition, a proton pump inhibitor was administered to wild-type mice to examine the contribution of gastric acid to emptying. RESULTS: Gastric emptying was significantly enhanced in mice lacking CCK-BR, as compared with wild-type and CCK-AR(-/-) mice. CCK-8S inhibited gastric emptying in mice with CCK-AR, but not in mice without CCK-AR. A proton pump inhibitor did not affect gastric emptying. Atropine dose dependently inhibited gastric emptying in all genotypes. The thickness of smooth muscle was comparable for all genotypes. CONCLUSIONS: The gastric emptying of a nonnutrient liquid load was enhanced in mice without CCK-BR, although the precise mechanism is not known. Although cholecystokinin (CCK) has been shown to inhibit gastric emptying via CCK-A receptors (CCK-ARs), the role of CCK-B receptors (CCK-BRs) has not been verified. We examined whether gastric emptying of a nonnutrient liquid load was modified in CCK-AR, BR, and ARBR gene knockout mice.

Animals↗