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Results for “knockout”

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At least 217 records · Page 12Linked to original sources

PubMed2005

Taurine-transporter gene knockout-induced changes in GABA(A), kainate and AMPA but not NMDA receptor binding in mouse brain.

The aim of this study was to determine whether the knockout of the taurine-transporter gene in the mouse affects the densities of GABA(A), kainate, AMPA and NMDA receptors in the brain. The caudate-putamen, the hippocampus and its subregions, and the cerebellum of six homozygous taurine-transporter gene knockout mice and six wild-type (WT) animals were examined by means of quantitative receptor autoradiography. Saturation studies were carried out for all four receptor types in order to find possible intergroup differences in Bmax and K(D) values. Taurine-transporter gene knockout animals showed significantly higher GABA(A) receptor densities in the molecular layer of the hippocampal dentate gyrus and in the cerebellum than did WT animals. The densities of kainate receptors were significantly higher in the caudate-putamen, the CA1 and hilus regions of the hippocampus and in the cerebellum of knockout animals. The caudate-putamen and cerebellum of these mice also contained significantly higher AMPA receptor densities. However, there were no significant differences between knockout and WT animals concerning the densities of NMDA receptors. Reduced brain taurine levels are associated with increased GABA(A), kainate and AMPA receptor densities in some of the regions we examined.

Animals↗

PubMed2002

Peroxisome proliferator-activated receptor alpha,gamma coagonist LY465608 inhibits macrophage activation and atherosclerosis in apolipoprotein E knockout mice.

The apolipoprotein E (apoE) knockout mouse has provided an approach to the investigation of the effect of both cellular and humoral processes on atherosclerotic lesion progression. In the present study, pharmacologic modulation of both interferon gamma (IFNgamma)-inducible macrophage effector functions, and atherosclerotic lesions in the apoE knockout mouse were investigated using the peroxisome proliferator-activated receptor (PPAR) alpha,gamma coagonist LY465608. LY465608 inhibited, in a concentration-dependent manner, IFNgamma induction of both nitric oxide synthesis and the beta 2 integrin CD11a in elicited peritoneal macrophages from apoE knockout mice. Similar effects were observed ex vivo following 10 d of treating mice with 10 mg/kg of LY465608. Treatment of apoE knockout mice for 18 wk with LY465608 resulted in a statistically significant 2.5-fold reduction in atherosclerotic lesion area in en face aorta preparations. These effects were apparent in the absence of any reduction in total serum cholesterol or in lipoprotein distribution. Finally, treatment of apoF knockout mice with established atherosclerotic disease resulted in a modest but not statistically significant decrease in aortic lesional surface area. These results demonstrate the utility of PPAR coagonists in reducing the progression of the atherosclerotic lesion.

Animals↗

PubMed2004

Exercise normalises overexpression of TNF-alpha in knockout mice.

TNF-alpha is linked with insulin resistance, as greater amounts of TNF are detected in muscle and adipose tissue in glycemically challenged people and TNF-alpha inhibits insulin receptor signalling. However, what modulates this overexpression of TNF-alpha is currently unknown. We examined the effect of 1 h exercise on overexpression of the TNF-alpha gene in TNF receptor 1 and 2 knockout mice. IL-6 knockout mice were included to elucidate the importance of IL-6 in regulating TNF-alpha in response to exercise. TNF-alpha gene expression was over-expressed in muscle in both TNFR knockout models. TNF-alpha overexpression returned to normal levels after exercise in the TNF-alpha receptor knockout models. In IL-6 knockout mice, a modest decrease in TNF-alpha was also observed. These data suggest that TNF-alpha-induced insulin resistance can be regulated by a single exercise bout by normalising TNF-alpha expression. This exercise effect can be mediated via IL-6, but also an IL-6 independent mechanism seems to exist.

Adipose Tissue↗

PubMed2004

Impaired motor performance and learning in glia maturation factor-knockout mice.

Glia maturation factor (GMF) is a unique brain protein localized in astrocytes and some neuronal populations. Studies with overexpression of GMF using adenovirus vector have uncovered its regulatory role in intracellular signal transduction and downstream induction of biologically active molecules, including the neurotrophins and cytokines. The current paper deals with the behavior of mice devoid of GMF protein (knockout). GMF-null mice developed normally without gross abnormality. When tested for simple position discrimination using a T-maze and for spatial memory using a Morris water maze, the knockout mice performed as well as the wild-type, showing no defect in maze learning. However, with beam walking, GMF-knockout mice performed poorly and failed to learn. Knockout mice were also defective in learning the eyeblink classical conditioning. Histologically, the knockout mice showed a loss of neurons in the inferior olive, which is a component of the circuitry of eyeblink conditioning, and is also essential for motor performance. The structural abnormality in GMF-null mice explained their impaired ability for both motor performance and motor learning.

Animals↗

PubMed2004

Methamphetamine sensitization in nociceptin receptor knockout mice: locomotor and c-fos expression.

The role of endogenous nociceptin in the development and expression of sensitization to repeated methamphetamine administration in a novel environment was studied in nociceptin receptor knockout mice. No differences in acute or sensitized locomotor responses were found in nociceptin receptor knockout mice. However, analysis of c-fos expression revealed significant interactions between chronic methamphetamine treatment and genotype in the nucleus accumbens and lateral septum. This was due to increased c-fos expression in chronically methamphetamine-treated nociceptin receptor knockout mice contrasted with reduced c-fos expression in chronically vehicle-treated nociceptin receptor knockout mice. Two further regions (nucleus accumbens core and ventromedial caudate putamen) showed significant interactions between genotype, chronic, and acute methamphetamine treatment due to accentuated c-fos expression in nociceptin receptor knockout mice sensitized and challenged with methamphetamine. These findings suggest endogenous nociceptin modulates the response of the central nervous system to repeated psychostimulant administration, although this is little reflected in locomotion.

Animals↗

PubMed2004

Changes in acetylcholinesterase activity and muscarinic receptor bindings in mu-opioid receptor knockout mice.

Anatomical evidence indicates that cholinergic and opioidergic systems are co-localized and acting on the same neurons. However, the regulatory mechanisms between cholinergic and opioidergic system have not been well characterized. In the present study, we investigated whether there are compensatory changes of acetylcholinesterase activity and cholinergic receptors in mice lacking mu-opioid receptor gene. The acetylcholinesterase activity was determined by histochemistry assay. The cholinergic receptor binding was carried out by quantitative autoradiography using [3H]-quinuclidinyl benzilate (nonselective muscarinic receptors), N-[3H]-methylscopolamine (nonselective muscarinic receptors), [3H]-pirenzepine (M1 subtype muscarinic receptors) and [3H]-AF-DX384 (M2 subtype muscarinic receptors) in brain slices of wild-type and mu-opioid receptor knockout mice. The acetylcholinesterase activity of mu-opioid receptor knockout mice was higher than that of the wild-type in the striatal caudate putamen and nucleus accumbens, but not in the cortex and hippocampus areas. In addition, the bindings in N-[3H]-methylscopolamine and [3H]-AF-DX384 of mu-opioid receptor knockout mice were significantly lower when compared with that of the wild-type controls in the striatal caudate putamen and nucleus accumbens. However, there were no significant differences in bindings of [3H]-quinuclidinyl benzilate and [3H]-pirenzepine between mu-opioid receptor knockout and wild-type mice in the cortex, striatum and hippocampus. These data indicate that there are up-regulation of acetylcholinesterase activity and compensatory down-regulation of M2 muscarinic receptors in the striatal caudate putamen and nucleus accumbens of mu-opioid receptor knockout mice.

Acetylcholinesterase↗

PubMed2005

Aspartoacylase gene knockout results in severe vacuolation in the white matter and gray matter of the spinal cord in the mouse.

Canavan disease (CD) is a neurodegenerative disorder characterized by the spongy degeneration of the white matter of the brain. Aspartoacylase (ASPA) gene mutation resulting enzyme deficiency is the basic cause of CD. Whether the ASPA defect in CD affects the spinal cord has been investigated using the ASPA gene knockout mouse. Luxol fast blue-hematoxylin and eosin staining in the spinal cord of the knockout mouse showed vacuolation in both white matter and gray matter areas of cervical, thoracic, lumbar, and sacral segments of the spinal cord. However, more vacuoles were seen in the gray matter than the white matter of the spinal cord. ASPA activity in the cervical, thoracic, lumbar, and sacrococcygeal regions of the spinal cord was significantly lower in the knockout mouse compared to the wild type. The enzyme defect in the knockout mouse was also confirmed using the Western blot method. These observations suggest that the ASPA gene defect in the mouse leads to spinal cord pathology, and that these changes may be partly involved in the cause of the physiological/behavioral abnormalities seen in the knockout mouse, if documented also in patients with CD.

Amidohydrolases↗

PubMed2006

Exocytotic release of dopamine in ventral tegmental area slices from C57BL/6 and dopamine transporter knockout mice.

The present study used voltammetry to ascertain whether electrically stimulated somatodendritic dopamine release in ventral tegmental area slices from C57BL/6 and dopamine transporter knockout mice was due to exocytosis or dopamine transporter reversal, as has been debated. The maximal concentration of electrically evoked dopamine release was similar between ventral tegmental area slices from dopamine transporter knockout and C57BL/6 mice. Dopamine transporter blockade (10 microM nomifensine) in slices from C57BL/6 mice inhibited dopamine uptake but did not alter peak evoked dopamine release. In addition, dopamine release and uptake kinetics in ventral tegmental area slices from dopamine transporter knockout mice were unaltered by the norepinephrine transporter inhibitor, desipramine (10 microM), or the serotonin transporter inhibitor, fluoxetine (10 microM). Furthermore, maximal dopamine release in ventral tegmental area slices from both C57BL/6 and dopamine transporter knockout mice was significantly decreased in response to Na(+) channel blockade by 1 microM tetrototoxin, removal of Ca(2+) from the perfusion media and neuronal vesicular monoamine transporter inhibition by RO-04-1284 (10 microM) or tetrabenazine (10 and 100 microM). Finally, the glutamate receptor antagonists AP-5 (50 and 100 microM) and CNQX (20 and 50 microM) had no effect on peak somatodendritic dopamine release in C57BL/6 mice. Overall, these data suggest that similar mechanisms, consistent with exocytosis, govern electrically evoked dopamine release in ventral tegmental area slices from C57BL/6 and dopamine transporter knockout mice.

Animals↗

PubMed2005

Increased sensitivity to acute and persistent pain in neuron-specific endothelin-1 knockout mice.

Endothelin-1 (ET-1) exists in endothelial cells as well as a variety of other cell types. The presence of ET-1 and its receptors in neurons suggests its possible role as a neurotransmitter and/or neuromodulator. Studies utilizing exogenous ET-1 have suggested that ET-1 affects pain transmission. This study was designed to examine the possible role(s) of neuronal ET-1 in pain processing. We produced neuron-specific ET-1 knockout mice using the Cre/loxP system with a synapsin I promoter and examined the effects produced by the lack of neuronal ET-1 on pain behavior using common pain models and a model of stress-induced analgesia. In acute nociceptive pain models, paw withdrawal thresholds to radiant heat and mechanical stimuli applied with von Frey hairs were significantly lower in the knockout mice compared with control. This indicated that the absence of neuronal ET-1 leads to greater sensitivity to acute nociceptive stimuli. After inflammation was produced by intraplantar injection of carrageenan, there was a significantly greater degree of thermal hyperalgesia and mechanical allodynia in the knockout mice even after the difference in baseline values was compensated. Furthermore, in a neuropathic pain model produced by spinal nerve ligation, there was also a greater degree of mechanical allodynia in the knockout mice. Finally, in a swim-stress model, the magnitude of stress-induced analgesia was less in the knockout mice, indicating the involvement of neuronal ET-1 in stress-induced analgesia. The results suggest that there is a basal release of ET-1 from neurons that affect baseline pain thresholds as well as an additional release during persistent pain states that acts to suppress the pain. The involvement of neuronal ET-1 in stress-induced analgesia further suggests its role in endogenous pain inhibitory systems. To confirm that ET-1 is released in persistent pain states and to determine which part of the CNS is involved, we measured the concentrations of ET-1 before and after inducing peripheral inflammation in different parts of the CNS involved in endogenous pain inhibitory systems in normal mice. We found that ET-1 was increased in the hypothalamus while no significant increase was observed in the midbrain, medulla and spinal cord. The results of the present study suggest that neuronal ET-1 is involved in endogenous pain inhibitory control likely via pathways through the hypothalamus.

Acute Disease↗

PubMed2000

Stress-induced analgesia in mu-opioid receptor knockout mice reveals normal function of the delta-opioid receptor system.

Stress-induced analgesia (SIA) was examined in wildtype and mu-opioid receptor knockout mice. We used thermal paw withdrawal (TPW) latency following a continuous 3-min swim in 20 degrees C water, and found a significant increase in TPW latency in both wild-type and knockout mice. Pre-treatment prior to the swim with naltrindole, a selective delta-opioid receptor antagonist, blocked the increase in TPW latency in knockout mice. These results demonstrate an intact delta-receptor-mediated function of a physiologically-released endogenous agonist in the mu-opioid receptor knockout mouse. The present findings are in contrast with previous reports that analgesia induced by exogenous delta agonists is reduced in the knockout mice.

Analgesia↗

PubMed2003

5-HT1A receptor knockout mouse as a genetic model of anxiety.

Low levels of the serotonin(1A) (5-HT(1A)) receptor have been repeatedly found in mood and anxiety disorders. Stress often exacerbates psychiatric disease and can also reduce 5-HT(1A) receptor levels. When receptor deficiency was produced in mice by genetic knockout, an anxiety-like phenotype was observed. Anxiety in mice is defined as a high level of avoidance of novel and unfamiliar environment and increased fear reaction. Other aspects of anxiety such as autonomic activation, increased stress responsiveness, and neuroendocrine abnormalities have also been described in receptor knockout mice. These data indicate that 5-HT(1A) receptor knockout mice represent a genetic animal model of anxiety with both construct and face validities. Although the core phenotype of anxiety can be reproduced in knockout mice in various inbred and outbred backgrounds, abnormalities in 5-HT dynamics and resistance to the anxiolitic drug diazepam have been seen in one but not on other genetic backgrounds. This indicates that while the development of anxiety is an invariable consequence of receptor deficit, other features induced by receptor loss are strongly modulated by other gene(s). Strain-dependent variability within the core phenotype does not diminish the value of 5-HT(1A) receptor knockout mice as a model of anxiety. Indeed, it is consistent with the manifestation of anxiety in genetically heterogeneous human population.

Animals↗

PubMed1998

Genetic analysis of NOS isoforms using nNOS and eNOS knockout animals.

All three major isoforms of nitric oxide synthase (NOS) are expressed in the brain. Because of complex and overlapping expression patterns (Marletta, 1994; Nathan and Xie, 1994), the particular NOS isoform involved in many processes is not clear. In fact, NO generated by separate isoforms may have different roles and potentially opposing effects (Iadecola et al., 1994). We have taken a genetic approach, to disrupt or knockout the genes for NOS isoforms to circumvent some of the limitations of pharmacologic agents. This approach allows the study of each individual NOS isoform in physiologic processes in the context of intact animals. It gives insights into possible developmental roles for NO and parallel processes that may compensate for the absence of each NOS isoform. We have made nNOS and eNOS knockout mice, as well as double knockout mice that lack both nNOS and eNOS isoforms (Huang et al., 1993; Huang et al., 1995; Son et al., 1996). In this chapter, we review some of the physiologic roles for NO that have been elucidated making use of these mice, including regulation of cerebral blood flow, response to cerebral ischemia, regulation of neurotransmitter release in the brain, and development of synaptic plasticity. Other chapters will discuss results using NOS knockout animals in studies of long term potentiation (see Hawkins, this volume), neuronal development (see Mize, this volume), and potential mechanisms for protection in nNOS knockout mice (Moskowitz, M.A.; Dawson, V.L, this volume).

Animals↗

PubMed2001

Plasticity in serotonin uptake in primary neuronal cultures of serotonin transporter knockout mice.

The cross talk between dopaminergic and serotonergic systems in the brain has multiple neurophysiological and behavioral implications. Primary neuronal cultures of embryonic wild type (+/+) and serotonin transporter knockout (-/-) mice were used as a model to elucidate the possibility of plasticity at the level of serotonin uptake. Serotonergic neurons were identified in midbrain-hindbrain cultures of both wild type and knockout mice, using polyclonal anti-serotonin antibodies. Adding serotonin (10 microM) to wild type midbrain-hindbrain cultures increased the intensity of serotonin immunostaining, but did not change the number of serotonergic neurons. This increased intensity of serotonin staining was blocked by the serotonin transporter inhibitors fluoxetine and imipramine, but not with the dopamine transporter inhibitor nomifensine. In serotonin transporter knockout cultures, however, serotonin increased both the intensity of serotonin immunostaining and the number of serotonin positive neurons, and nomifensine decreased the number of serotonin-labeled neurons. Uptake of [3H]serotonin to wild type midbrain-hindbrain cultures was completely blocked by 1 microM fluoxetine, whereas nomifensine had a very small effect. In contrast, [3H]serotonin uptake to serotonin transporter knockout cultures, although very weak, was better inhibited by nomifensine than fluoxetine. The results imply that midbrain-hindbrain neuronal cultures of knockout mice, that do not express serotonin transporters, acquire the capacity to take up serotonin, apparently via dopamine transporters.

Adrenergic Uptake Inhibitors↗

PubMed2003

IL-2 gene knockout affects T lymphocyte trafficking and the microglial response to regenerating facial motor neurons.

Following facial nerve axotomy in mice, T cells cross the intact blood-brain barrier (BBB), home to nerve cell bodies in the facial motor nucleus (FMN), and augment neuroregenerative processes. The pivotal T cell immunoregulatory cytokine, IL-2, appears to have bidirectional effects on neuronal and microglial cell function, suggesting rival hypotheses that IL-2 could either enhance or disrupt processes associated with regeneration of axotomized facial motor neurons. We tested these competing hypotheses by comparing the effect of facial nerve axotomy on C57BL/6-IL-2(-/-) knockout and C57BL/6-IL-2(+/+) wild-type littermates. Since IL-2 may also be produced endogenously in the brain, we also sought to determine whether differences between the knockout and wild-type mice were attributable to loss of IL-2 gene expression in the CNS, loss of peripheral sources of IL-2 and the associated effects on T cell function, or a combination of these factors. To address this question, we bred novel congenic mice with the SCID mutation (mice lacking T cell derived IL-2) that were homozygous for either the IL-2 knockout or wild-type gene alleles (C57BL/6scid-IL-2(-/-) and C57BL/6scid-IL-2(+/+) littermates, respectively). Groups were assessed for differences in (1) T lymphocytes entering the axotomized FMN; (2) perineuronal CD11b(+) microglial phagocytic clusters, a measure of motor neuron death; and (3) activated microglial cells as measured by MHC-II positivity. C57BL/6-IL-2(-/-) knockout mice had significantly higher numbers of T cells and lower numbers of activated MHC-II-positive microglial cells in the regenerating FMN than wild-type littermates, although the number of CD11b(+) phagocytic microglia clusters did not differ. Thus, despite the significant impairment of T cell function known to be associated with loss of peripheral IL-2, the increased number of T cells entering the axotomized FMN appears to have sufficient activity to support neuroregenerative processes. Congenic C57BL/6scid-IL-2(-/-) knockout mice had lower numbers of CD11b(+) microglial phagocytic clusters than congenic C57BL/6scid-IL-2(+/+) wild-type littermates, suggesting that loss of the IL-2 gene in the CNS (and possibly the loss of other unknown sources of the gene) enhanced neuronal regeneration. Further study of IL-2's complex actions in neuronal injury may provide greater understanding of key variables that determine whether or not immunological processes in the brain are proregenerative.

Animals↗

PubMed2000

Spatial learning, contextual fear conditioning and conditioned emotional response in Fmr1 knockout mice.

Fmr1 knockout mice are an animal model for fragile X syndrome, the most common form of heritable mental retardation in humans. Fmr1 knockout mice exhibit macro-orchidism and cognitive and behavioural deficits reminiscent of the human phenotype. In the present study additional behavioural and cognitive testing was performed. Knockouts and control littermates were subjected to a spatial learning test using a plus-shaped water maze. Animals had to learn the position of a hidden escape platform during training trials. The position of this platform was changed during subsequent reversal trials. Previously reported deficits in reversal learning were replicated, but we also observed significant differences during the acquisition trials. A plus-shaped water maze experiment with daily changing platform positions failed to provide clear evidence for a working memory impairment, putatively underlying the spatial learning deficits. Two different test settings were used to examine the reported deficit of Fmr1 knockout mice in fear conditioning. Conditioned fear responses were observed in a contextual fear test, and the ability to acquire an emotional response was tested by means of response suppression in a conditioned emotional response procedure. Neither protocol revealed significant differences between controls and knockouts.

Acoustic Stimulation↗

PubMed2002

Cardiac function in neuropeptide Y Y4 receptor-knockout mice.

Autonomic control of cardiovascular function in neuropeptide Y (NPY) Y4 receptor-knockout mice was investigated using pancreatic polypeptide (PP), NPY and specific agonists and antagonists for other NPY receptors well characterised in cardiovascular function. Y4 receptor-knockout mice, anaesthetised with sodium pentobarbitone, displayed slower heart rate, indicated by a higher pulse interval and lower blood pressure compared to control mice. After vagus nerves were cut heart rate increased but was still significantly slower than in control mice. PP had no effect on blood pressure or cardiac vagal activity in either group of mice, which was consistent with earlier studies in other species. Injection of NPY evoked an increase in blood pressure but the response was significantly reduced in Y4 receptor-knockout mice compared to the controls. The reduction in pressor activity was not Y1 mediated as the selective Y1 antagonist, BIBP 3226, was effective in blocking NPY pressor activity in knockout mice. In addition, cardiac vagal inhibitory activity evoked by low doses of NPY was also reduced when compared to control responses. As N-acetyl [Leu(28, 31)] NPY 24-36 inhibited vagal activity dose dependently in both groups of mice with no difference in response at any dose, it is unlikely that this effect also is receptor mediated. We propose that the reduced vasoconstrictor and vagal inhibitory activity evoked by NPY in Y4 receptor-knockout mice is due to a lack of adrenergic tone bought about by a proposed reduction in sympathetic activity, possibly resulting from altered NPY activity secondarily affecting adrenergic transmission. We conclude that Y4 receptor deletion disrupts autonomic balance within the cardiovascular system.

Animals↗

PubMed2001

Pituitary-specific knockout of steroidogenic factor 1.

Knockout mice lacking the orphan nuclear receptor steroidogenic factor 1 (SF-1) revealed its essential roles at multiple levels of endocrine development and function. These SF-1 knockout mice lacked adrenal glands and gonads, thereby manifesting adrenal insufficiency and sex reversal of their internal and external genitalia. Their pituitary gonadotropes failed to express several markers of normal differentiated function, and they lacked a specific hypothalamic nucleus, the ventromedial hypothalamic nucleus (VMH). Using the Cre-loxP system, we generated mice whose gene encoding SF-1 was inactivated specifically in the anterior pituitary. These pituitary-specific SF-1 knockout mice were sterile and never matured sexually. Their gonads weighed only approximately 5% of the weight of wild-type gonads. SF-1 immunoreactivity was absent in the anterior pituitary but was unaffected in the adrenal cortex, validating the selectivity of the gene targeting strategy. Consistent with an important role of SF-1 in gonadotropes, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were markedly decreased in the pituitary-specific SF-1 knockout mice. The pituitary-specific SF-1 knockout mice are a novel genetic model of hypogonadotropic hypogonadism and establish essential roles of SF-1 in gonadotropin expression.

Animals↗

PubMed2003

Differential effects of morphine and cocaine on locomotor activity and sensitization in mu-opioid receptor knockout mice.

The present study was undertaken to investigate the hypothesis that the mu-opioid receptors play a crucial role in locomotor activity and sensitization to cocaine and morphine in wild-type and mu-opioid receptor knockout mice. Our results show that morphine and cocaine increased locomotor activity in wild-type mice, but failed to increase locomotor activity in mu-opioid receptor knockout mice, suggesting a contribution of mu-opioid receptor. Repeated morphine treatment induced sensitization in wild-type mice, but this was not observed in mu-opioid receptor knockout mice. In contrast repeated cocaine treatment produced sensitization in mu-opioid receptor knockout mice, but not in wild-type mice on day 6. However, the sensitization to cocaine was observed in mu-opioid receptor knockout and wild-type mice on day 12. These results suggest that the expression of mu-opioid receptor may contribute to locomotor sensitization induced by morphine, but that mu-opioid receptor does not play an important role in mediating sensitization to cocaine.

Adaptation, Physiological↗