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PubMed1998

Metallothionein knockout and transgenic mice exhibit altered intestinal processing of zinc with uniform zinc-dependent zinc transporter-1 expression.

A role for metallothionein in intestinal zinc absorption has been the subject of considerable debate. If metallothionein affects zinc absorption, then those factors that induce metallothionein synthesis (e.g., heavy metals, hormones) should alter zinc absorption and homeostasis. The present studies used metallothionein transgenic mice (overexpressing) and metallothionein knockout mice (no expression of metallothionein-1 or metallothionein-2) to examine directly the effects of metallothionein on zinc absorption, independent of secondary effects that could be caused by metallothionein inducers. Zinc absorption was examined by administering a single oral zinc dose (0.5 mmol/kg) by feeding tube to metallothionein transgenic and metallothionein knockout mice and measuring the serum zinc concentration. Two hours after the dose, the serum zinc concentration was 2.3 times higher in metallothionein knockout mice than in their control strain. Conversely, the concentration was elevated only one third as much in the metallothionein transgenic mice as in their controls after the zinc dose. We found that the serum zinc concentration was inversely related to the level of metallothionein protein. The intestinal zinc content was higher in the metallothionein knockout mice, however, suggesting that metallothionein did not reduce zinc absorption by simply sequestering zinc in the mucosa. The expression of the zinc transporter ZnT-1 was directly related to the serum zinc level and was independent of the level of metallothionein. These results further support metallothionein as an important component for reducing the efficiency of zinc absorption at elevated zinc intakes.

Animals↗

PubMed2001

Metallothionein expression protects against carbon tetrachloride-induced hepatotoxicity, but overexpression and dietary zinc supplementation provide no further protection in metallothionein transgenic and knockout mice.

Metallothionein and zinc have been implicated in cellular defense against a number of cytotoxic agents. With respect to the free radical-generating hepatotoxin carbon tetrachloride, conclusions about a defensive role were reached from in vitro studies, in vivo studies using inducers of metallothionein and studies using injections of pharmacological amounts of zinc. Metallothionein knockout (null) and metallothionein transgenic mice are more direct models to examine the effects of metallothionein expression on induced cytotoxicity. Similarly, zinc presented via the diet is a more physiological model than that presented via injection. We examined whether metallothionein-overexpressing mice or metallothionein knockout mice had altered sensitivity to carbon tetrachloride and whether supplemental dietary zinc reduced sensitivity to carbon tetrachloride in these genotypes. Metallothionein knockout mice produced no metallothionein and were unable to sequester additional hepatic zinc in response to elevated dietary zinc. Hepatotoxicity, as measured by serum alanine aminotransferase activity, histological analyses and hepatic thiol levels, was greater in the knockout mice than in controls 12 h after carbon tetrachloride treatment but not at later time points (up to 48 h). In contrast, metallothionein-overexpressing mice produced more metallothionein and sequestered more liver zinc than control mice, but hepatotoxicity was similar between genotypes. Supplemental dietary zinc had no effect on hepatotoxicity with either genotype. These data suggest metallothionein null mice were more susceptible to carbon tetrachloride-induced hepatotoxicity than were control mice. However, neither metallothionein overexpression nor supplemental dietary zinc provided further protection.

Alanine Transaminase↗

PubMed2002

The neuronal migration defect in mice with Zellweger syndrome (Pex5 knockout) is not caused by the inactivity of peroxisomal beta-oxidation.

The purpose of this study was to investigate whether deficient peroxisomal beta-oxidation is causally involved in the neuronal migration defect observed in Pex5 knockout mice. These mice are models for Zellweger syndrome, a peroxisome biogenesis disorder. Neocortical development was evaluated in mice carrying a partial or complete defect of peroxisomal beta-oxidation at the level of the second enzyme of the pathway, namely, the hydratase-dehydrogenase multifunctional/bifunctional enzymes MFP1/L-PBE and MFP2/D-PBE. In contrast to patients with multifunctional protein 2 deficiency who present with neocortical dysgenesis, impairment of neuronal migration was not observed in the single MFP2 or in the double MFP1/MFP2 knockout mice. At birth, the double knockout pups displayed variable growth retardation and about one half of them were severely hypotonic, whereas the single MFP2 knockout animals were all normal in the perinatal period. These results indicate that in the mouse, defective peroxisomal beta-oxidation does not cause neuronal migration defects by itself. This does not exclude that the inactivity of this metabolic pathway contributes to the brain pathology in mice and patients with complete absence of functional peroxisomes.

Animals↗

PubMed1998

Oligonephronia, not exuberant apoptosis, accounts for the development of glomerulosclerosis in the bcl-2 knockout mouse.

BACKGROUND: A main function attributed to B cell leukaemia/lymphoma 2 gene (bcL-2) is its ability to confer resistance against apoptosis. In bcl-2 deficient mice, extensive apoptosis occurs during abnormal nephrogenesis, and renal failure is found very quickly after birth. However, the underlying mechanisms remain poorly understood. The aim of the present study was to clarify whether the degenerative process in the kidneys seen after birth is based either on increased apoptosis of glomerular cells or on mechanisms independent from the genetic defect. MATERIALS AND METHODS: Kidneys from 7-56-day-old bcl-2 knockout mice and wild-type litter mates were studied. Glomerular number, glomerular tuft volume, cell counts in 'non-sclerotic' glomeruli as well as the glomerular damage score were determined by histomorphometrical studies. Apoptosis was evaluated by morphological criteria and the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL)-technique. RESULTS: The number of nephrons at birth was severely decreased in bcl-2 knockout mice compared to controls (<20%; P < 0.001). These nephrons undergo dramatic hypertrophy with an approximately 4-fold increase in volume (P < 0.001). In hypertrophic, but 'non-sclerotic' glomeruli, the number density of glomerular cells progressively declined with time (P<0.001). Starting with day 20, enlarged glomeruli developed sclerosis beginning with a segmental distribution, but quickly progressing to global sclerosis. Apoptosis was neither detected in non-sclerotic glomeruli nor in stages prior to fully established sclerosis. As shown by the glomerular damage score, post-natal degeneration of kidneys from bcl-2 knockout animals proceeded rapidly. CONCLUSIONS: Bcl-2 knockout mice exhibit deficient nephrogenesis resulting in severe oligonephronia at birth. Post-partum development of glomerulosclerosis does not seem to be due to augmented apoptosis. The degenerative process appears to be based on a glomerular overload with increased mechanical stress to the filtration barrier, leading via glomerular hypertrophy, podocyte damage and formation of tuft adhesions to glomerulosclerosis.

Animals↗

PubMed1996

Meiotic abnormalities of c-mos knockout mouse oocytes: activation after first meiosis or entrance into third meiotic metaphase.

In Xenopus oocytes, Mos activates the mitogen-activated protein kinase (MAPK) signal transduction cascade and regulates meiosis. In mammalian oocytes, however, the functions of Mos are still unclear. In the present study, we used c-mos knockout mouse oocytes and examined the roles of Mos in mouse oocyte maturation and fertilization, including whether Mos controls MAPK and maturation promoting factor (MPF) activity. The kinetics of germinal vesicle breakdown (GVBD) and the first polar body emission were similar in wild-type, heterozygous mutant, and homozygous mutant mice. Activities of MPF were also not significantly different among the three genotypes until the first polar body emission. In contrast, MAPK activity in c-mos knockout oocytes did not significantly fluctuate throughout maturation, and the oocytes had abnormal diffused spindles and loosely condensed chromosomes, although a clear increase in MAPK activities was observed after GVBD in wild-type and heterozygous mutant oocytes that had normal spindles and chromosomes. After the first polar body emission, 38% of c-mos knockout oocytes formed a pronucleus instead of undergoing second meiosis, indicating the crucial role of Mos in MPF reactivation after first meiosis. When oocytes that reached second metaphase were fertilized or stimulated by ethanol, many c-mos knockout oocytes emitted a second polar body and progressed into third meiotic metaphase instead of interphase, although all fertilized or activated oocytes in the heterozygote progressed to interphase, indicating that Mos deletion leads to compensatory factors that might not be degraded after fertilization or parthenogenetic activation. These results suggest that Mos is located upstream of MAPK in mouse oocytes as in Xenopus oocytes but is independent of MPF activity, and that Mos/MAPK is not necessary go GVBD and first polar body emission. Our results also suggest that Mos plays a crucial role in normal spindle and chromosome morphology and the reactivation of MPF after first meiosis.

Animals↗

PubMed1999

Infertile spermatozoa of c-ros tyrosine kinase receptor knockout mice show flagellar angulation and maturational defects in cell volume regulatory mechanisms.

Homozygous c-ros knockout male mice that lack prepubertal differentiation of the epididymal initial segment are healthy but sterile, despite normal sperm production and mating. Detailed computerized analysis of the motility of spermatozoa maturing in the epididymis revealed only minor defects. However, the majority of motile mature sperm released from the cauda epididymidis showed various extents of flagellar angulation that could not be corrected by raising extracellular osmolality. Measurement of the osmolality of cauda epididymal fluid showed no difference from the wild type. Studies in wild-type mice indicated a maturational change in the ability of motile sperm to maintain straight flagella during incubation, but angulation was induced in cauda sperm by the volume-sensitive ion channel blockers quinine, 5-nitro-2-(3-phenylpropylamino)-benzoic acid and BaCl(2), or by exposure to hypotonic media. Flagellar angulation, induced in the wild type or intrinsic to the knockout, was relieved upon demembranation by Triton X-100, confirming that it was a cell swelling phenomenon. A lack of response of immature wild-type sperm and mature knockout sperm to the channel blockers suggests that there is normally a development of the volume regulatory mechanisms upon maturation that is defective in sperm from the knockout animal. The resultant flagellar angulation may account for the reduction in sperm numbers in the oviduct of mated females and the failure to fertilize in vivo.

Animals↗

PubMed2026

Conditional eIF2A Deletion Suggests Extra-Adipose Mechanisms Underlying Metabolic Syndrome in Total-Body eIF2A Knockout Mice.

Dynamic regulation of protein synthesis is essential for metabolic homeostasis, with translation initiation playing a key role in this process. Emerging evidence strongly indicates that in addition to canonical eukaryotic initiation factors (e.g., eIF2, eIF4E) non-canonical factors, such as eukaryotic initiation factor 2A can modulate metabolic homeostasis. eIF2A is a highly conserved eukaryotic protein originally proposed to function analogously to bacterial IF2, promoting initiator Met-tRNAi recruitment to the 40S ribosomal subunit, though its precise mechanism remains debated. To investigate its organismal role, we have previously generated the total-body eIF2A knockout mouse, which revealed eIF2A functions in lipid homeostasis, glucose tolerance, insulin sensitivity, and susceptibility to metabolic syndrome. To further determine whether adipose tissue drives these phenotypes, we presently generated adipose-specific eIF2A knockout mice. Despite dysregulation of some key adipokines, including for example, adiponectin, these mice did not develop metabolic syndrome, even under high-fat diet conditions, indicating that adipose tissue specific deficiency of eIF2A is insufficient to reproduce the metabolic defects observed in total-body knockout. However, we found that eIF2A deficiency in the liver of the total body eIF2A-KO mice can independently drive metabolic syndrome components via translational control of Lpin1 (a phosphatidate phosphatase and a transcriptional coactivator) that controls hepatic lipid storage and metabolism. eIF2A deficiency in the liver leads to disruption of fatty acid oxidation and the production of ketone bodies, not observed in adipose-specific eIF2A knockout mice. Our findings suggest that systemic metabolic effects observed in the total body eIF2A-KO mice may arise from coordinated functions across multiple organs.

adipose tissue↗

PubMed2006

Gene knockout of the KCNJ8-encoded Kir6.1 K(ATP) channel imparts fatal susceptibility to endotoxemia.

Sepsis, the systemic inflammatory response to infection, imposes a high demand for bodily adaptation, with the cardiovascular response a key determinant of outcome. The homeostatic elements that secure cardiac tolerance in the setting of the sepsis syndrome are poorly understood. Here, in a model of acute septic shock induced by endotoxin challenge with Escherichia coli lipopolysaccharide (LPS), knockout of the KCNJ8 gene encoding the vascular Kir6.1 K(ATP) channel pore predisposed to an early and profound survival disadvantage. The exaggerated susceptibility provoked by disruption of this stress-responsive sensor of cellular metabolism was linked to progressive deterioration in cardiac activity, ischemic myocardial damage, and contractile dysfunction. Deletion of KCNJ8 blunted the responsiveness of coronary vessels to cytokine- or metabolic-mediated vasodilation necessary to support myocardial perfusion in the wild-type (WT), creating a deficit in adaptive response in the Kir6.1 knockout. Application of a K(ATP) channel opener drug improved survival in the endotoxic WT but had no effect in the Kir6.1 knockout. Restoration of the dilatory capacity of coronary vessels was required to rescue the Kir6.1 knockout phenotype and reverse survival disadvantage in lethal endotoxemia. Thus, the Kir6.1-containing K(ATP) channel, by coupling vasoreactivity with metabolic demand, provides a vital feedback element for cardiovascular tolerance in endotoxic shock.

Animals↗

PubMed1999

Murine mentors: transgenic and knockout models of surgical disease.

OBJECTIVE: Transgenic and knockout technologies have emerged from the "molecular biology revolution" as unprecedented techniques for manipulating gene function in intact mice. The goals of this review are to outline the techniques of creating transgenic and knockout mice, and to demonstrate their use in elucidation of the molecular mechanisms underlying common surgical diseases. SUMMARY BACKGROUND DATA: Gain of gene function is created by transgenic technology, whereas gene function is ablated using gene knockouts. Each technique has distinctive applications and drawbacks. A unique feature of genetically manipulated mice is that combinatorial genetic experiments can be executed that precisely define the functional contribution of a gene to disease progression. Transgenic and knockout mouse models of wound healing, cardiovascular disease, transplant immunology, gut motility and inflammatory bowel disease, and oncology are beginning to illuminate the precise molecular regulation of these diseases. Transgenic technology has also been extended to larger mammals such as pigs, with the goal of using genetic manipulation of the xenogenic immune response to increase the availability of transplant organs. Continual refinements in gene manipulation technology in mice offer the opportunity to turn genes on or off at precise time intervals and in particular tissues, according to the needs of the investigator. Ultimately, investigation of disease development and progression in genetically manipulated mammals may delineate new molecular targets for drug discovery and provide novel platforms for drug efficacy screens. CONCLUSIONS: Emulation of human disease and therapy using genetically manipulated mammals fulfills a promise of molecular medicine: fusion of molecular biochemistry with "classical" biology and physiology. Surgeons have unique skills spanning both worlds that can facilitate their success in this expanding arena.

Animals↗

PubMed2001

Matrix metalloproteinase 2 gene knockout has no effect on acute brain injury after focal ischemia.

Matrix metalloproteinases (MMPs) may contribute to tissue damage after cerebral ischemia. In this study, wildtype and MMP-2 knockout mice were subjected to permanent and transient (2 h) occlusions of the middle cerebral artery. Gelatin zymography showed that MMP-9 levels were increased in all brains after ischemia. MMP-2 levels did not show a significant increase in wildtype mice, and were not detectable in knockout mice. Laser doppler flowmetry demonstrated equivalent ischemic reductions in perfusion in wildtype and knockout mice. In both permanent and transient occlusion paradigms, there were no statistically significant differences between wildtype and knockout mice in terms of 24 h ischemic lesion volumes. These data suggest that MMP-2 does not contribute to acute tissue damage in this model of focal ischemia.

Animals↗

PubMed2003

Unaltered expression of Bcl-2 and TAG-1/axonin-1 precedes sensory apoptosis in Brn3a knockout mice.

Mice lacking the POU-domain transcription factor Brn3a exhibit growth defects in trigeminal axons, undergo extensive sensory cell death in late gestation, and die at birth. Based on tissue culture studies, the mediator of apoptosis Bcl-2 has been suggested as a target of Brn3a regulation which could affect sensory viability in these mice. In addition, Bcl-2 and the neural cell adhesion molecule TAG-1/axonin-1 have both been implicated in sensory axon guidance. In this study we examined wild-type and Brn3a knockout embryos for alterations in the expression of these genes. Trigeminal ganglia were harvested from embryonic day 13.5 mouse embryos, and Bcl-2 and TAG-1 expression were measured by RT-PCR. TAG-1 expression was also examined in the embryonic trigeminal and dorsal root ganglia by immunohistochemistry. The developing trigeminal ganglia of Brn3a knockout mice exhibit similar levels of Bcl-2 and TAG-1 mRNA expression. Immunohistochemical staining of TAG-1 also appeared to be quantitatively similar in the sensory axons of wild-type and knockout embryos. It is unlikely that Bcl-2 is a regulatory target of Brn3a, or that either of these factors mediates the defects in axon guidance and neuronal survival observed in the sensory ganglia of Brn3a knockout mice.

Animals↗

PubMed2000

Inducible nitric oxide synthase gene knockout mice have increased resistance to gut injury and bacterial translocation after an intestinal ischemia-reperfusion injury.

OBJECTIVE: Intestinal ischemia-reperfusion after severe shock states is often associated with bacterial translocation and intestinal barrier dysfunction. Our previous studies showed that inducible nitric oxide synthase (iNOS) gene knockout mice were resistant to endotoxin-induced bacterial translocation and ileal mucosal damage. The goal of this study was to test whether iNOS mediates bacterial translocation after intestinal ischemia-reperfusion, using iNOS knockout mice (iNOS-/-) and their wild-type littermates (iNOS+/+). DESIGN: Prospective animal study with concurrent controls. SETTING: Small animal laboratory. SUBJECTS: Thirty-eight iNOS knockout mice and 51 wild-type littermates. INTERVENTIONS: iNOS+/+ mice or iNOS-/- mice were subjected to a sham operation or 30 mins of superior mesenteric artery occlusion followed by reperfusion. Twenty-four hours after reperfusion, bacterial translocation to mesenteric lymph nodes, ileal villous damage, and cecal bacterial population were evaluated. MEASUREMENTS AND MAIN RESULTS: Sham operation did not induce bacterial translocation, change cecal bacterial population levels, or cause ileal villous damage. Intestinal ischemia-reperfusion caused bacterial translocation in 72% of the iNOS+/+ mice but only 28% of the iNOS-/- mice. Both iNOS+/+ and iNOS-/- mice subjected to superior mesenteric artery occlusion (SMAO) in which bacterial translocation occurred had cecal bacterial population levels that were three logs higher than mice subjected to sham SMAO or mice subjected to SMAO in which bacterial translocation did not occur. The magnitude of villous injury was less in the iNOS-/- mice than the iNOS+/+ mice after SMAO, although the incidence of ileal villous damage was significantly higher in both the iNOS+/+ and iNOS-/- mice in which bacterial translocation occurred after SMAO than in the mice in which bacterial translocation did not occur after SMAO. iNOS+/+ mice subjected to SMAO had increased plasma concentrations of nitrite (NO2-) and nitrate (NO3-), and the plasma concentrations of NO2- and NO3- were highest in the mice in which bacterial translocation had occurred. CONCLUSION: iNOS knockout mice were more resistant to intestinal ischemia-reperfusion-induced bacterial translocation and mucosal injury than wild-type mice, suggesting that iNOS might play a role in intestinal ischemia-reperfusion-induced loss of gut barrier function.

Animals↗

PubMed2005

Changes in signaling pathways regulating neuroplasticity induced by neurokinin 1 receptor knockout.

Neurokinin 1 (NK-1) receptor knockout mice showed behavioral responses similar to animals chronically treated with antidepressants. The aim of this study was to analyse, in NK-1 receptor knockout, the molecular modifications of signaling pathways involved in the pathophysiology of depression and antidepressant mechanism. We found, in total cell cytosol from the prefrontal/frontal cortex, hippocampus and striatum, a marked up-regulation of Ca(2+)-independent enzymatic activity and Thr(286) autophosphorylation of Ca(2+)/calmodulin-dependent protein kinase (CaMK) II. Similar changes in CaMKII regulation were previously observed in rats chronically treated with antidepressants. In striatum, up-regulation of the activity and phosphorylation of CaMKII was also found in the homogenate and synaptosomes. No major changes were observed in the Ca(2+)-dependent kinase activity, with the exception of homogenate from the prefrontal/frontal cortex. We also analysed the expression and phosphorylation of presynaptic proteins, which modulate synaptic vesicle trafficking and exocytosis, and found a marked decrease in synapsin I total expression and basal phosphorylation of Ser(603) (the phosphorylation site for CaMKII) in the prefrontal/frontal cortex. Accordingly, the Ca(2+)/calmodulin-dependent posthoc endogenous phosphorylation of synapsin I in the same area was increased. The knockout of NK-1 receptor had no consequences on the expression or phosphorylation levels of the transcription factor cAMP-responsive element-binding protein and its regulating kinase CaMKIV. However, phosphorylation of ERK1/2-mitogen-activated protein kinases was reduced in the hippocampus and striatum, again resembling an effect previously observed in antidepressant-treated rats. These results show similarities between NK-1 knockouts and animals chronically treated with antidepressants and support the putative antidepressant activity of NK-1 receptor antagonists.

Animals↗

PubMed2006

Ontogeny of brain and blood serotonin levels in 5-HT receptor knockout mice: potential relevance to the neurobiology of autism.

The most consistent neurochemical finding in autism has been elevated group mean levels of blood platelet 5-hydroxytryptamine (5-HT, serotonin). The origin and significance of this platelet hyperserotonemia remain poorly understood. The 5-HT(1A) receptor plays important roles in the developing brain and is also expressed in the gut, the main source of platelet 5-HT. Post-natal tissue levels of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) and tryptophan were examined in the brain, duodenum and blood of 5-HT(1A) receptor-knockout and wild-type mice. At 3 days after birth, the knockout mice had lower mean brain 5-HT levels and normal mean platelet 5-HT levels. Also, at 3 days after birth, the mean tryptophan levels in the brain, duodenum and blood of the knockout mice were around 30% lower than those of the wild-type mice. By 2 weeks after birth, the mean brain 5-HT levels of the knockout mice normalized, but their mean platelet 5-HT levels became 24% higher than normal. The possible causes of these dynamic shifts were explored by examining correlations between central and peripheral levels of 5-HT, 5-HIAA and tryptophan. The results are discussed in relation to the possible role of 5-HT in the ontogeny of autism.

Animals↗

PubMed2004

Histochemical examination of periodontal junctional epithelium in p21/p27 double knockout mice.

The periodontal junctional epithelium (JE) is maintained in a steady state through a dynamic process that balances proliferation and exfoliation of epithelial cells. However, mechanisms that regulate JE are not well understood. To better understand how proliferation of the JE is controlled in healthy gingiva, we have studied functional roles of the CDK (cyclin dependent kinase) inhibitors p21 and p27 in JE using knockout mouse model systems. Image analysis of the dentogingival junction in p21 or p27 single knockout mice as well as p21/p27 double knockout mice (dKO) was performed. The analysis revealed enlarged JE in p21/p27 dKO mice due to an increase in the area of the epithelium and associated connective tissue 'islands'. Immunohistochemistry was performed for p21, p27, cyclin D1, and proliferating cell nuclear antigen (PCNA). The highest levels of PCNA-positive cells were detected in the p21/p27 dKO mice, reflecting increased cell turnover. Lower levels of cyclin D1 were detected in the JE of p21/p27 knockout mice, suggesting that p21 and p27 regulate stability of cyclin D1 in oral epithelium. These data suggest that p21 and p27 have a critical role in controlling epithelial cell proliferation in the JE and thus function to maintain the JE at a normal size.

Animals↗

PubMed2006

Melatonin reduces infarction volume in a photothrombotic stroke model in the wild-type but not cyclooxygenase-1-gene knockout mice.

Cyclooxygenase (COX)-2 plays a harmful role in cerebral ischemic/reperfusion injury, but the role of COX-1 is uncertain. In the present study, cerebral infarct was induced by photothrombosis. Intraperitoneal injections of melatonin at 15 g/kg or its vehicle were made at 0.5 hr before stroke and 24 and 48 hr after stroke. Cerebral blood flow (CBF) in the penumbra was monitored during stroke using a laser Doppler flowmeter. Sensorimotor behavior was evaluated using the turning in an alley and falling from a pole tests at 1 hr before stroke and 24 and 48 hr after stroke. Infarct volume was determined from the T2-weighted magnetic resonance images at 72 hr after stroke. During the first 15 min of stroke, CBF decreased in the penumbra in both homozygous COX-1-gene knockout and wild-type mice. Melatonin treatment improved the penumbral CBF in the wild-type mice. Mild poststroke impairment in sensorimotor behavior was detected by the turning in an alley test in which the COX-1-gene knockout mice performed better. Melatonin treatment did not affect the poststroke sensorimotor behavior. The relative infarct volume at 72 hr after stroke was 8.1% and 8.4% in the COX-1-gene knockout and wild-type mice, respectively. Melatonin treatment reduced the relative infarct volume to 6.3% in the latter but not in the former (8.2%). Thus, COX-1-gene knockout does not affect the brain's susceptibility to photothrombotic stroke. Melatonin treatment reduces infarct size in the wild-type mice following photothrombotic stroke partly via maintenance of penumbral CBF in which the COX-1-gene may play a role.

Animals↗

PubMed1998

5-HT1B receptor modulation of prepulse inhibition: recent findings in wild-type and 5-HT1B knockout mice.

Sensorimotor gating of the startle reflex occurs when the presentation of a weak "prepulse" 30-500 msec prior to a startling stimulus inhibits the reflex, and is called prepulse inhibition (PPI). The study of PPI has recently been extended to mice to take advantage of recent advances in molecular genetics, because several neuropsychiatric disorders including schizophrenia, obsessive compulsive disorder, and schizotypal personality disorder are characterized by PPI deficits. Studies in wild-type and 5-HT1B knockout mice suggest that activation of 5-HT1B receptors decreases PPI. The direct 5-HT1A/1B agonist RU24969 decreases PPI in wild-type but not 5-HT1B knockout mice. Likewise, the serotonin releasing compounds MDMA(+), MBDB(+/-), and alpha-ethyltryptamine (AET) have no effect on PPI in wild-type mice, but increase PPI in 5-HT1B knockout mice. As the direct 5-HT1A agonist 8-OH-DPAT increases PPI in mice, the unmasking of these effects may also contribute to the PPI-increasing effects of 5-HT releasers in 5-HT1B knockout mice.

Animals↗

PubMed2004

Cochlear function in Prestin knockout mice.

Gross-potential recordings in mice lacking the Prestin gene indicate that compound action potential (CAP) thresholds are shifted by approximately 45 dB at 5 kHz and by approximately 60 dB at 33 kHz. However, in order to conclude that outer hair cell (OHC) electromotility is associated with the cochlear amplifier, frequency selectivity must be evaluated and the integrity of the OHC's forward transducer ascertained. The present report demonstrates no frequency selectivity in CAP tuning curves recorded in homozygotes. In addition, CAP input-output functions indicate that responses in knockout mice approach those in controls at high levels where the amplifier has little influence. Although the cochlear microphonic in knockout mice remains approximately 12 dB below that in wild-type mice even at the highest levels, this deficit is thought to reflect hair cell losses in mice lacking prestin. A change in OHC forward transduction is not implied because knockout mice display non-linear responses similar to those in controls. For example, homozygotes exhibit a bipolar summating potential (SP) with positive responses at high frequencies; negative responses at low frequencies. Measurement of intermodulation distortion also shows that the cubic difference tone, 2f(1)-f(2), is approximately 20 dB down from the primaries in both homozygotes and their controls. Because OHCs are the sole generators of the negative SP and because 2f(1)-f(2) is also thought to originate in OHC transduction, these data support the idea that forward transduction is not degraded in OHCs lacking prestin. Finally, application of AM1-43, which initially enters hair cells through their transducer channels, produces fluorescence in wild-type and knockout mice indicating transducer channel activity in both inner and outer hair cells.

Acoustic Stimulation↗