The Experts below are selected from a list of 174 Experts worldwide ranked by ideXlab platform
Wolfgang Löscher - One of the best experts on this subject based on the ideXlab platform.
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The circling ci2 Rat Mutant revisited: receptor architecture of the motor cortex.
Neuroscience, 2010Co-Authors: Nicola Palomero-gallagher, Axel Schleicher, Karl Zilles, Wolfgang LöscherAbstract:Abstract Circling behaviour of the ci2 Rat Mutant has been associated with an abnormal laterality concerning nigrostriatal and vestibular dopamine content and densities of several neurotransmitter receptors. Since not only subcortical, but also cortical activity subserve behavioural asymmetry, we applied quantitative in vitro receptor autoradiography to determine the densities of twenty neurotransmitter receptors in three areas of the motor cortex (Fr1, Fr2, Fr3) of the left and right hemispheres in adult male circling Mutant Rats ( ci2 / ci2 ), non-circling littermates ( ci2 /+) and aged-matched Rats from the background strain (LEW/Ztm, wild type). Rats had previously been monitored for motor behaviour and swimming abilities. Wild type and ci2 /+ Rats did not differ from the behavioural point of view, whereas ci2 / ci2 animals were characterized by pronounced lateralized circling behaviour and were not able to perform the swimming test correctly. Left Fr2 of wild type Rats contained significantly lower NMDA receptor densities than its right counterpart. No interhemispheric differences were found in the motor cortex of ci2 /+ or ci2 / ci2 animals. All three areas of wild type Rats contain higher GABA A and adenosine A 1 receptor densities than those of ci2 /+ and ci2 / ci2 animals, respectively. Serotonin 5-HT 2 receptor densities were significantly lower in the motor cortex of ci2 / ci2 animals than in that of their heterozygous littermates. Thus, since the ci2 Rat Mutant presents a wide range of behavioural and neurochemical lateralization anomalies, in addition to representing a model of Usher syndrome type 1, it may prove useful to understand the mechanisms underlying abnormal rotational behaviour and its relevance as a model of disturbances in cerebral asymmetry and their consequences.
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Auditory and vestibular defects and behavioral alteRations after neonatal administRation of streptomycin to Lewis Rats: Similarities and differences to the circling (ci2/ci2) Lewis Rat Mutant.
Brain research, 2007Co-Authors: Marko Schirmer, Alexander Kaiser, Maren Fedrowitz, Alina Lessenich, Sven Lindemann, Manuela Gernert, Wolfgang LöscherAbstract:The clinical usefulness of aminoglycoside antibiotics is limited by their ototoxicity. In rodents, damage to the inner ear is often associated with rotational behavior and locomotor hyperactivity reminiscent of such behaviors resulting from an imbalance of forebrain dopamine systems. Based on previous observations in the circling (ci2/ci2) Lewis (LEW) Rat Mutant, a spontaneous mutation leading to hair cell loss, deafness, impairment of vestibular functions, lateralized circling, hyperactivity and alteRations in the nigrostriatal dopamine system, we have recently hypothesized that vestibular defects during postnatal development, independent of whether induced or inherited, lead to secondary changes in the dopaminergic system within the basal ganglia, which would be a likely explanation for the typical behavioral phenotype seen in such models. In the present study, we directly compared the phenotype induced by streptomycin in LEW Rats with that of the ci2 LEW Rat Mutant. For this purpose, we treated neonatal LEW Rats over 3 weeks by streptomycin, which induced bilateral degeneRation of cochlear and vestibular hair cells. Following this treatment period, the behavioral syndrome of the streptomycin-treated animals, including the lateralized rotational behavior, was almost indistinguishable from that of ci2 Mutant Rats. However, in contrast to the ci2 Mutant Rat, all alteRations, except the hearing loss, were only transient, disappearing between 7 and 24 weeks following treatment. In conclusion, in line with our hypothesis, vestibular defects induced in normal LEW Rats led to the same phenotypic behavior as the inherited vestibular defect of ci2 Mutant Rats. However, with increasing time for recovery, adaptation to the vestibular impairment developed in streptomycin-treated Rats, while all deficits persisted in the Mutant animals. At least in part, the transient nature of the abnormal behaviors resulting from treatment with streptomycin could be explained by adaptation to the vestibular impairment by the use of visual cues, which is not possible in ci2 Rats because of progressive retinal degeneRation in these Mutants. Although further experiments are needed to prove this hypothesis, the present study shows that direct comparisons between these two models serve to understand the mechanisms underlying the complex behavioral phenotype in rodents with vestibular defects and how these defects are compensated.
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AlteRations in dopamine D3 receptors in the circling (ci3) Rat Mutant.
Neuroscience, 2006Co-Authors: M. Schirmer, José N. Nobrega, S.j. Harrison, Wolfgang LöscherAbstract:Abstract We have previously described a black-hooded Mutant Rat (BH.7A/Ztm- ci3/ci3 ) that displays abnormal lateralized circling behavior, but normal auditory and vestibular functions. Neurochemical determination of dopamine and dopamine metabolite levels in striatum, nucleus accumbens and substantia nigra showed that ci3 Rats have a significant asymmetry in striatal dopamine in that dopamine levels were significantly lower in the hemisphere contralateral to the preferred direction of turning. Consistent with this finding, immunohistological examination of dopaminergic neurons in substantia nigra and ventral tegmental area yielded a significant laterality in the medial part of substantia nigra pars compacta with a lower density of tyrosine hydroxylase-positive neurons in the contralateral hemisphere of Mutant circling Rats, while no laterality was seen in unaffected Rats of the background strain. In the present study, quantitative autoradiography was used to examine the binding of [ 3 H]SCH 23390, [ 3 H]raclopride and [ 3 H]7-OH-DPAT (7-hydroxy-N,N-di-n-propyl-2-aminotetralin) to dopamine D1, D2, and D3 receptors, respectively, in various brain regions of ci3 Rats and unaffected Rats of the background strain (BH.7A(LEW)/Won). No significant differences between circling Rats and controls were obtained for D1 and D2 receptor binding in any region, but Mutant Rats differed from controls in dopamine D3 binding in several regions. A significant decrease in D3 binding was seen in the shell of the nucleus accumbens, the islands of Calleja, and the subependymal zone of ci3 Mutant Rats. Furthermore, a significant laterality in D3 binding was determined in ci3 Rats in that binding was lower in the contralateral hemisphere in the shell of the nucleus accumbens and the islands of Calleja. Our data indicate that alteRations of dopamine D3 receptors may be involved in the behavioral phenotype of the ci3 Rat, thus substantiating the findings from a recent genetic linkage analysis that indicated the D3 receptor gene as a candidate gene in this Rat Mutant.
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Altered spontaneous discharge Rate and pattern of basal ganglia output neurons in the circling (ci2) Rat Mutant
Neuroscience, 2003Co-Authors: Maren Fedrowitz, Wolfgang Löscher, Sven Lindemann, Manuela GernertAbstract:The circling Rat is an autosomal recessive Mutant (homozygous ci2/ci2) characterized by lateralized rotational behavior, locomotor hyperactivity, ataxia, stereotypic head movements, and deafness. Previous neurochemical investigations showed that ci2 Rats of both genders have a lower tissue content of dopamine in the striatum ipsilateral to the preferred direction of circling. For further evaluation as to whether this striatal imbalance has functional consequences within basal ganglia structures, the spontaneous extracellular single unit activity of GABAergic neurons located in the striatum and, downstream to the dopaminergic nigrostriatal system, the substantia nigra pars reticulata (SNr) was recorded bilaterally in anesthetized ci2 Rats. Heterozygous (ci2/+) littermates that display normal behavior, and Rats from the background strain (LEW/Ztm) served as controls. No significant hemispheric imbalances in striatal discharge Rate and firing pattern were evident in ci2 Rats. Furthermore, there were no significant intergroup differences in striatal activity. However, the mean spontaneous discharge Rate of SNr neurons was significantly increased in both brain sides, and there was a significant shift toward rhythmic burst-like firing in ci2 Mutants. Again, no hemispheric differences were detected. The data substantiate previous findings of altered basal ganglia function in ci2 Rats. The abnormal basal ganglia output activity, i.e. of the SNr, is likely to contribute to the complex behavioral disturbances seen in ci2 Rats.
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Auditory and vestibular defects in the circling (ci2) Rat Mutant.
The European journal of neuroscience, 2001Co-Authors: Alexander Kaiser, Maren Fedrowitz, Ulrich Ebert, Elke Zimmermann, Hans-jürgen Hedrich, Dirk Wedekind, Wolfgang LöscherAbstract:The circling Rat is an autosomal recessive Mutant (homozygous ci2/ci2) that displays lateralized circling behaviour, locomotor hyperactivity, ataxia and stereotypic head-movement. These abnormal behaviours occur in phases or bursts either spontaneously or in response to stress. Heterozygous (ci2/+) littermates display normal spontaneous behaviours. We have previously found that ci2/ci2 Rats of both genders have a lower tissue content of dopamine in the striatum ipsilateral to the preferred direction of rotation, indicating that the Rats turn away from the brain hemisphere with higher striatal dopaminergic activity. In view of the similarities of the motor syndrome of the ci2/ci2 Mutant Rat to that of mouse deafness Mutants, the present study evaluated the hearing ability of the circling Rat Mutant by recording brainstem auditory-evoked potentials. To test for vestibular dysfunction, a swimming test was conducted. Histological methods were used to examine the cochlear and vestibular parts of the inner ear and the cochlear and vestibular brainstem nuclei for defects. The absence of auditory-evoked potentials demonstRated a complete hearing loss in the adult ci2/ci2 Mutant Rat, whereas heterozygous littermates exhibited auditory-evoked potentials with thresholds resembling those of other laboRatory strains. Furthermore, the Mutant Rats were unable to swim. Histological analysis of the inner ear of adult Mutants revealed virtually complete loss of the cochlear neuroepithelium, while no such hair cell degeneRation was seen in the vestibular parts of the inner ear. However, part of the vestibular hair cells showed protrusions into the endolymphatic space, suggesting alteRations in the cytoskeletal architecture. The histological findings in Mutant circling Rats strongly indicate that the hearing loss of the Mutants is of the sensory neural type, the most prevalent type of hearing loss. In the cochlear nuclei of the brain stem of Mutant Rats, neurons exhibited an abnormal shape, reduced size and increased density compared to controls. In contrast, no abnormal neuronal morphology was seen in the vestibular nuclei, but a significantly reduced neuronal density was found in the medial vestibular nucleus. Abnormal vestibular function would be a likely explanation for the disturbed balance of Mutant Rats as exemplified by the ataxia and the inability to swim, whereas the previous data on these Rats strongly indicate an involvement of the basal ganglia in the abnormal circling behaviour. The genetic defect in the Mutant Rats, thus, results in a clinical syndrome with features also seen in human genetic disorders with deafness and hyperkinesia, making the ci2/ci2 Rat an excellent model for investigating both cochlear/vestibular dysfunction and hyperkinetic movement disorders.
Warunee Dansithong - One of the best experts on this subject based on the ideXlab platform.
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spontaneous shaker Rat Mutant a new model for x linked tremor ataxia
Disease Models & Mechanisms, 2016Co-Authors: Karla P. Figueroa, Sharan Paul, Tito Calì, Raffaele Lopreiato, Sukanya Karan, Martina Frizzarin, Darren Ames, Ginevra Zanni, Marisa Brini, Warunee DansithongAbstract:ABSTRACT The shaker Rat is an X-linked recessive spontaneous model of progressive Purkinje cell (PC) degeneRation exhibiting a shaking ataxia and wide stance. GeneRation of Wistar Furth (WF)/Brown Norwegian (BN) F1 hybrids and genetic mapping of F2 sib-sib offspring using polymorphic markers narrowed the candidate gene region to 26 Mbp denoted by the last recombinant genetic marker DXRat21 at 133 Mbp to qter (the end of the long arm). In the WF background, the shaker mutation has complete penetrance, results in a stereotypic phenotype and there is a narrow window for age of disease onset; by contrast, the F2 hybrid phenotype was more varied, with a later age of onset and likely non-penetrance of the mutation. By deep RNA-sequencing, five variants were found in the candidate region; four were novel without known annotation. One of the variants caused an arginine (R) to cysteine (C) change at codon 35 of the ATPase, Ca 2+ transporting, plasma membrane 3 ( Atp2b3 ) gene encoding PMCA3 that has high expression in the cerebellum. The variant was well supported by hundreds of overlapping reads, and was found in 100% of all affected replicas and 0% of the wild-type (WT) replicas. The mutation segregated with disease in all affected animals and the amino acid change was found in an evolutionarily conserved region of PMCA3. Despite strong genetic evidence for pathogenicity, in vitro analyses of PMCA3 R35C function did not show any differences to WT PMCA3. Because Atp2b3 mutation leads to congenital ataxia in humans, the identified Atp2b3 missense change in the shaker Rat presents a good candidate for the shaker Rat phenotype based on genetic criteria, but cannot yet be considered a definite pathogenic variant owing to lack of functional changes.
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Spontaneous shaker Rat Mutant – a new model for X-linked tremor/ataxia
Disease models & mechanisms, 2016Co-Authors: Karla P. Figueroa, Sharan Paul, Tito Calì, Raffaele Lopreiato, Sukanya Karan, Martina Frizzarin, Darren Ames, Ginevra Zanni, Marisa Brini, Warunee DansithongAbstract:ABSTRACT The shaker Rat is an X-linked recessive spontaneous model of progressive Purkinje cell (PC) degeneRation exhibiting a shaking ataxia and wide stance. GeneRation of Wistar Furth (WF)/Brown Norwegian (BN) F1 hybrids and genetic mapping of F2 sib-sib offspring using polymorphic markers narrowed the candidate gene region to 26 Mbp denoted by the last recombinant genetic marker DXRat21 at 133 Mbp to qter (the end of the long arm). In the WF background, the shaker mutation has complete penetrance, results in a stereotypic phenotype and there is a narrow window for age of disease onset; by contrast, the F2 hybrid phenotype was more varied, with a later age of onset and likely non-penetrance of the mutation. By deep RNA-sequencing, five variants were found in the candidate region; four were novel without known annotation. One of the variants caused an arginine (R) to cysteine (C) change at codon 35 of the ATPase, Ca 2+ transporting, plasma membrane 3 ( Atp2b3 ) gene encoding PMCA3 that has high expression in the cerebellum. The variant was well supported by hundreds of overlapping reads, and was found in 100% of all affected replicas and 0% of the wild-type (WT) replicas. The mutation segregated with disease in all affected animals and the amino acid change was found in an evolutionarily conserved region of PMCA3. Despite strong genetic evidence for pathogenicity, in vitro analyses of PMCA3 R35C function did not show any differences to WT PMCA3. Because Atp2b3 mutation leads to congenital ataxia in humans, the identified Atp2b3 missense change in the shaker Rat presents a good candidate for the shaker Rat phenotype based on genetic criteria, but cannot yet be considered a definite pathogenic variant owing to lack of functional changes.
Fumihiko Horio - One of the best experts on this subject based on the ideXlab platform.
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A newly established strain of spontaneously hypertensive Rat with a defect of ascorbic acid biosynthesis.
Life sciences, 2001Co-Authors: Fumihiko Horio, Atsushi Kakinuma, Kaori Hayashi, Takashi Mishima, Kumiko Takemori, Itsuki Oshima, Hiroyuki ItoAbstract:Abstract To investigate the effects of ascorbic acid deficiency on the pathogenesis of hypertension and/or its complications, we established a Rat strain with both genetic hypertension and a defect of ascorbic acid biosynthesis. The od gene (L-gulono-γ-lactone oxidase gene) of the ODS (Osteogenic Disorder Shionogi) Rat, which is a Rat Mutant unable to synthesize ascorbic acid, was introduced into spontaneously hypertensive Rats (SHR), and a novel congenic strain, SHR-od, was established. SHR-od showed scurvy when fed an ascorbic acid-free diet. Systolic blood pressure of male SHR-od began to increase at 9 weeks of age and reached 190–200 mmHg at 20 weeks of age. In 25-week-old SHR-od, ascorbic acid deficiency when fed an ascorbic acid-free diet for 6 weeks caused a remarkable reduction of blood pressure to lower than 110 mmHg. The wall to lumen Ratio of the testicular artery in ascorbic acid-deficient SHR-od was lower than that of the control Rats. When Rats were fed a diet supplemented with ascorbic acid (300 mg/kg), ascorbic acid concentRation in SHR-od was lower in the serum and liver than that in ODS Rats. These results indicate that ascorbic acid could be closely related to the development of hypertension in SHR-od. We believe that SHR-od will be a useful model for experimental studies on hypertension and its complications, since all of them suffer from hypertension spontaneously and the level of ascorbic acid deficiency in these Rats could be controlled at will both in concentRation and duRation.
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Bilirubin Oxidation Provoked by Endotoxins Treatment is Suppressed by Feeding Ascorbic Acid in a Rat Mutant Unable to Synthesize Ascorbic Acid
European journal of biochemistry, 1997Co-Authors: Tokio Yamaguchi, Tsuneo Hashizume, Makiko Tanaka, Mitsuyo Nakayama, Akiko Sugimoto, Saiko Ikeda, Hiroshi Nakajima, Fumihiko HorioAbstract:We examined the possibility that bilirubin oxidation is provoked in vivo by using scurvy-prone ODS-odlod Rats treated with endotoxins (lipopolysaccharide). Recently, bilirubin oxidative metabolites were isolated from human urine and named biotripyrrin-a and biotripyrrin-b. In ODS-odlod Rats fed in ascorbicacid-free diet, the concentRation of bilirubin metabolites in urine was increased 7.0-fold at 3 h after injection of lipopolysaccharide and 4.4-fold at 10 h compared to the control Rats injected with saline. The dietary supplement of ascorbic acid, the physiological antioxidant, suppressed the increase in bilirubin metabolites in urine after lipopolysaccharide injection: concentRations of biotripyrrin-a and biotripyrrin-b in urine collected 6.5–10 h after the injection were lower in Rats fed an ascorbic-acid-supplemented diet than in Rats f4ed an ascorbic-acid-free diet. Moreover, feeding of ascorbic acid suppressed the hepatic mRNA level of heme oxygenase-1, the Rate-limiting enzyme of bilirubin biosyntheses, in Rats injected with lipopolysaccharide. These findings indicate that bilirubin oxidation is markedly stimulated in lipopolysaccharide-treated Rats and suggest that bilirubin and ascorbic acid have physiologically protective effects against oxidative stress.
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Ascorbic acid deficiency elevates serum level of LDL-cholesterol in a Rat Mutant unable to synthesize ascorbic acid.
Journal of nutritional science and vitaminology, 1991Co-Authors: Fumihiko Horio, Yoshiyuki Hayashi, Naoko Takahashi, Akira YoshidaAbstract:The effect of ascorbic acid deficiency on serum levels of high density lipoprotein- (HDL-), low density lipoprotein- (LDL-), very low density lipoprotein- (VLDL-) and chylomicron-cholesterol was examined in ODS-od/od Rat (ODS Rat), that is a Rat Mutant unable to synthesize ascorbic acid. Male ODS Rats were fed an ascrobic acid-free diet for 20 days. In another two groups, the diet supplemented with 300mg ascorbic acid/kg diet was fed either ad libitum (ad libitum control) or in pair-feeding (pair-fed control). Pair-fed Rats received the same amount of diet as Rats fed the ascorbic acid-free diet. Serum level of total cholesterol in the ad libitum control Rats, ascorbic acid-deficient Rats, and the pair-fed control Rats were 100.1±8.4mg/dl, 92.8±6.2mg/dl and 72.2±4.8mg/dl, respectively. The level of LDL-cholesterol in ascorbic acid-deficient Rats was significantly higher than that in the ad libitum control or that in the pair-fed control. The level of HDL-cholesterol in ascorbic acid-deficient Rats was lower than that in the ad libitum control, but was not changed as compared with that in the pair-fed control. Ascorbic acid deficiency did not affect serum level of VLDL-cholesterol or chylomicron-cholesterol as compared with those in the controls. These results demonstRate that ascorbic acid deficiency causes the elevation of serum level of LDL-cholesterol both in ad libitum feeding condition and pair feeding condition.
Karla P. Figueroa - One of the best experts on this subject based on the ideXlab platform.
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spontaneous shaker Rat Mutant a new model for x linked tremor ataxia
Disease Models & Mechanisms, 2016Co-Authors: Karla P. Figueroa, Sharan Paul, Tito Calì, Raffaele Lopreiato, Sukanya Karan, Martina Frizzarin, Darren Ames, Ginevra Zanni, Marisa Brini, Warunee DansithongAbstract:ABSTRACT The shaker Rat is an X-linked recessive spontaneous model of progressive Purkinje cell (PC) degeneRation exhibiting a shaking ataxia and wide stance. GeneRation of Wistar Furth (WF)/Brown Norwegian (BN) F1 hybrids and genetic mapping of F2 sib-sib offspring using polymorphic markers narrowed the candidate gene region to 26 Mbp denoted by the last recombinant genetic marker DXRat21 at 133 Mbp to qter (the end of the long arm). In the WF background, the shaker mutation has complete penetrance, results in a stereotypic phenotype and there is a narrow window for age of disease onset; by contrast, the F2 hybrid phenotype was more varied, with a later age of onset and likely non-penetrance of the mutation. By deep RNA-sequencing, five variants were found in the candidate region; four were novel without known annotation. One of the variants caused an arginine (R) to cysteine (C) change at codon 35 of the ATPase, Ca 2+ transporting, plasma membrane 3 ( Atp2b3 ) gene encoding PMCA3 that has high expression in the cerebellum. The variant was well supported by hundreds of overlapping reads, and was found in 100% of all affected replicas and 0% of the wild-type (WT) replicas. The mutation segregated with disease in all affected animals and the amino acid change was found in an evolutionarily conserved region of PMCA3. Despite strong genetic evidence for pathogenicity, in vitro analyses of PMCA3 R35C function did not show any differences to WT PMCA3. Because Atp2b3 mutation leads to congenital ataxia in humans, the identified Atp2b3 missense change in the shaker Rat presents a good candidate for the shaker Rat phenotype based on genetic criteria, but cannot yet be considered a definite pathogenic variant owing to lack of functional changes.
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Spontaneous shaker Rat Mutant – a new model for X-linked tremor/ataxia
Disease models & mechanisms, 2016Co-Authors: Karla P. Figueroa, Sharan Paul, Tito Calì, Raffaele Lopreiato, Sukanya Karan, Martina Frizzarin, Darren Ames, Ginevra Zanni, Marisa Brini, Warunee DansithongAbstract:ABSTRACT The shaker Rat is an X-linked recessive spontaneous model of progressive Purkinje cell (PC) degeneRation exhibiting a shaking ataxia and wide stance. GeneRation of Wistar Furth (WF)/Brown Norwegian (BN) F1 hybrids and genetic mapping of F2 sib-sib offspring using polymorphic markers narrowed the candidate gene region to 26 Mbp denoted by the last recombinant genetic marker DXRat21 at 133 Mbp to qter (the end of the long arm). In the WF background, the shaker mutation has complete penetrance, results in a stereotypic phenotype and there is a narrow window for age of disease onset; by contrast, the F2 hybrid phenotype was more varied, with a later age of onset and likely non-penetrance of the mutation. By deep RNA-sequencing, five variants were found in the candidate region; four were novel without known annotation. One of the variants caused an arginine (R) to cysteine (C) change at codon 35 of the ATPase, Ca 2+ transporting, plasma membrane 3 ( Atp2b3 ) gene encoding PMCA3 that has high expression in the cerebellum. The variant was well supported by hundreds of overlapping reads, and was found in 100% of all affected replicas and 0% of the wild-type (WT) replicas. The mutation segregated with disease in all affected animals and the amino acid change was found in an evolutionarily conserved region of PMCA3. Despite strong genetic evidence for pathogenicity, in vitro analyses of PMCA3 R35C function did not show any differences to WT PMCA3. Because Atp2b3 mutation leads to congenital ataxia in humans, the identified Atp2b3 missense change in the shaker Rat presents a good candidate for the shaker Rat phenotype based on genetic criteria, but cannot yet be considered a definite pathogenic variant owing to lack of functional changes.
Maren Fedrowitz - One of the best experts on this subject based on the ideXlab platform.
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Auditory and vestibular defects and behavioral alteRations after neonatal administRation of streptomycin to Lewis Rats: Similarities and differences to the circling (ci2/ci2) Lewis Rat Mutant.
Brain research, 2007Co-Authors: Marko Schirmer, Alexander Kaiser, Maren Fedrowitz, Alina Lessenich, Sven Lindemann, Manuela Gernert, Wolfgang LöscherAbstract:The clinical usefulness of aminoglycoside antibiotics is limited by their ototoxicity. In rodents, damage to the inner ear is often associated with rotational behavior and locomotor hyperactivity reminiscent of such behaviors resulting from an imbalance of forebrain dopamine systems. Based on previous observations in the circling (ci2/ci2) Lewis (LEW) Rat Mutant, a spontaneous mutation leading to hair cell loss, deafness, impairment of vestibular functions, lateralized circling, hyperactivity and alteRations in the nigrostriatal dopamine system, we have recently hypothesized that vestibular defects during postnatal development, independent of whether induced or inherited, lead to secondary changes in the dopaminergic system within the basal ganglia, which would be a likely explanation for the typical behavioral phenotype seen in such models. In the present study, we directly compared the phenotype induced by streptomycin in LEW Rats with that of the ci2 LEW Rat Mutant. For this purpose, we treated neonatal LEW Rats over 3 weeks by streptomycin, which induced bilateral degeneRation of cochlear and vestibular hair cells. Following this treatment period, the behavioral syndrome of the streptomycin-treated animals, including the lateralized rotational behavior, was almost indistinguishable from that of ci2 Mutant Rats. However, in contrast to the ci2 Mutant Rat, all alteRations, except the hearing loss, were only transient, disappearing between 7 and 24 weeks following treatment. In conclusion, in line with our hypothesis, vestibular defects induced in normal LEW Rats led to the same phenotypic behavior as the inherited vestibular defect of ci2 Mutant Rats. However, with increasing time for recovery, adaptation to the vestibular impairment developed in streptomycin-treated Rats, while all deficits persisted in the Mutant animals. At least in part, the transient nature of the abnormal behaviors resulting from treatment with streptomycin could be explained by adaptation to the vestibular impairment by the use of visual cues, which is not possible in ci2 Rats because of progressive retinal degeneRation in these Mutants. Although further experiments are needed to prove this hypothesis, the present study shows that direct comparisons between these two models serve to understand the mechanisms underlying the complex behavioral phenotype in rodents with vestibular defects and how these defects are compensated.
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Altered spontaneous discharge Rate and pattern of basal ganglia output neurons in the circling (ci2) Rat Mutant
Neuroscience, 2003Co-Authors: Maren Fedrowitz, Wolfgang Löscher, Sven Lindemann, Manuela GernertAbstract:The circling Rat is an autosomal recessive Mutant (homozygous ci2/ci2) characterized by lateralized rotational behavior, locomotor hyperactivity, ataxia, stereotypic head movements, and deafness. Previous neurochemical investigations showed that ci2 Rats of both genders have a lower tissue content of dopamine in the striatum ipsilateral to the preferred direction of circling. For further evaluation as to whether this striatal imbalance has functional consequences within basal ganglia structures, the spontaneous extracellular single unit activity of GABAergic neurons located in the striatum and, downstream to the dopaminergic nigrostriatal system, the substantia nigra pars reticulata (SNr) was recorded bilaterally in anesthetized ci2 Rats. Heterozygous (ci2/+) littermates that display normal behavior, and Rats from the background strain (LEW/Ztm) served as controls. No significant hemispheric imbalances in striatal discharge Rate and firing pattern were evident in ci2 Rats. Furthermore, there were no significant intergroup differences in striatal activity. However, the mean spontaneous discharge Rate of SNr neurons was significantly increased in both brain sides, and there was a significant shift toward rhythmic burst-like firing in ci2 Mutants. Again, no hemispheric differences were detected. The data substantiate previous findings of altered basal ganglia function in ci2 Rats. The abnormal basal ganglia output activity, i.e. of the SNr, is likely to contribute to the complex behavioral disturbances seen in ci2 Rats.
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Auditory and vestibular defects in the circling (ci2) Rat Mutant.
The European journal of neuroscience, 2001Co-Authors: Alexander Kaiser, Maren Fedrowitz, Ulrich Ebert, Elke Zimmermann, Hans-jürgen Hedrich, Dirk Wedekind, Wolfgang LöscherAbstract:The circling Rat is an autosomal recessive Mutant (homozygous ci2/ci2) that displays lateralized circling behaviour, locomotor hyperactivity, ataxia and stereotypic head-movement. These abnormal behaviours occur in phases or bursts either spontaneously or in response to stress. Heterozygous (ci2/+) littermates display normal spontaneous behaviours. We have previously found that ci2/ci2 Rats of both genders have a lower tissue content of dopamine in the striatum ipsilateral to the preferred direction of rotation, indicating that the Rats turn away from the brain hemisphere with higher striatal dopaminergic activity. In view of the similarities of the motor syndrome of the ci2/ci2 Mutant Rat to that of mouse deafness Mutants, the present study evaluated the hearing ability of the circling Rat Mutant by recording brainstem auditory-evoked potentials. To test for vestibular dysfunction, a swimming test was conducted. Histological methods were used to examine the cochlear and vestibular parts of the inner ear and the cochlear and vestibular brainstem nuclei for defects. The absence of auditory-evoked potentials demonstRated a complete hearing loss in the adult ci2/ci2 Mutant Rat, whereas heterozygous littermates exhibited auditory-evoked potentials with thresholds resembling those of other laboRatory strains. Furthermore, the Mutant Rats were unable to swim. Histological analysis of the inner ear of adult Mutants revealed virtually complete loss of the cochlear neuroepithelium, while no such hair cell degeneRation was seen in the vestibular parts of the inner ear. However, part of the vestibular hair cells showed protrusions into the endolymphatic space, suggesting alteRations in the cytoskeletal architecture. The histological findings in Mutant circling Rats strongly indicate that the hearing loss of the Mutants is of the sensory neural type, the most prevalent type of hearing loss. In the cochlear nuclei of the brain stem of Mutant Rats, neurons exhibited an abnormal shape, reduced size and increased density compared to controls. In contrast, no abnormal neuronal morphology was seen in the vestibular nuclei, but a significantly reduced neuronal density was found in the medial vestibular nucleus. Abnormal vestibular function would be a likely explanation for the disturbed balance of Mutant Rats as exemplified by the ataxia and the inability to swim, whereas the previous data on these Rats strongly indicate an involvement of the basal ganglia in the abnormal circling behaviour. The genetic defect in the Mutant Rats, thus, results in a clinical syndrome with features also seen in human genetic disorders with deafness and hyperkinesia, making the ci2/ci2 Rat an excellent model for investigating both cochlear/vestibular dysfunction and hyperkinetic movement disorders.
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Immunohistochemical and neurochemical studies on nigral and striatal functions in the circling (ci) Rat, a genetic animal model with spontaneous rotational behavior
Neuroscience, 1999Co-Authors: Angelika Richter, José N. Nobrega, Maren Fedrowitz, Ulrich Ebert, J.j. Vallbacka, Wolfgang LöscherAbstract:Asymmetrical spontaneous turning behavior or circling phenomena are often related to components of the dopaminergic system, particularly to an imbalance of nigrostriatal function. When a rotational preference is observed, it is typically in a direction away from the brain hemisphere with higher striatal dopaminergic transmission. We have recently described a Rat Mutant (ci) with spontaneous circling behavior and other signs of functional brain asymmetry. Neurochemical determinations showed that Mutants of both genders have significantly lower concentRations of dopamine and dopamine metabolites in the striatum ipsilateral to the preferred direction of rotation. In the present study, we used immunohistochemical, neurochemical, and autoradiographic techniques to characterize the dopaminergic abnormalities of the ci Rat Mutant in more detail. Age-matched non-affected controls of the same strain were used for comparison. Immunohistochemical labeling of dopaminergic neurons and fibers in substantia nigra pars compacta, ventral tegmental area, and striatum did not indicate any significant neurodegeneRation or asymmetry that could explain the lateralization in dopamine levels in striatum of ci Rats. Neurochemical determinations substantiated that ci Rats of both genders have a significant imbalance in striatal dopamine metabolism, but a similar significant lateralization was also seen in non-affected female controls. Comparison of dopamine, serotonin, noradrenaline and several monoamine metabolite levels in substantia nigra, striatum, nucleus accumbens and frontal cortex of ci Rats and controls did not disclose any marked difference between affected and non-affected animals which was consistently found in both genders. Quantitative autoradiographic determination of binding densities of dopamine transporter and D1 and D2 receptors in several parts of the striatum and substantia nigra indicated that ci Rats have a significantly higher binding density of dopamine transporter and receptors than controls. Taken together, ci Mutant Rats of both genders exhibit an asymmetry in striatal dopamine and metabolite levels and an enhanced dopamine transporter and receptor binding, but the link of these differences in dopaminergic parameters with the rotational behavior of the animals is not clear yet. The lack of any significant dopaminergic cell loss in the substantia nigra and the locomotor hyperactivity observed in the Mutants clearly suggest that the ci Rat is not suited as a model of Parkinsonism but Rather constitutes a model of a hyperkinetic motor syndrome.
