Rats with Congenital Tremor and Curled Whiskers and Hair

Yamada, Junzo; Serikawa, Tadao; Ishiko, Jiro; Inui, Toshiya; Takada, Hiroshi; Kawai, Yosuke; Okaniwa, Azusa

doi:10.1538/expanim1978.34.2_183

Cited by 52 publications

(34 citation statements)

References 3 publications

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“…The tremor rat (tm/tm) was first discovered as a genetic mutant in the inbred colony of Kyoto:Wistar rats and was shown to experience spontaneous seizures plus spongiform degeneration in the central nervous system (CNS) [1,2]. The genetic defect in these animals involves deletion of the aspartoacylase (ASPA; N-acetyl-L-aspartate amidohydrolase) gene, a feature that has made it a naturally occurring model of Canavan disease.…”

Section: Introductionmentioning

confidence: 99%

Myelin Lipid Abnormalities in the Aspartoacylase-Deficient Tremor Rat

Wang

Leone

et al. 2008

Neurochem Res

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The high concentration of N-acetylaspartate (NAA) in neurons of the central nervous system and its growing clinical use as an indicator of neuronal viability has intensified interest in the biological function of this amino acid derivative. The biomedical relevance of such inquiries is highlighted by the myelin-associated pathology of Canavan disease, an inherited childhood disorder resulting from mutation of aspartoacylase (ASPA), the NAA-hydrolyzing enzyme. This enzyme is known to be localized in oligodendrocytes with bimodal distribution in cytosol and the myelin sheath, and to produce acetyl groups utilized in myelin lipid synthesis. Loss of this acetyl source in Canavan disease and rodent models such as the tremor rat are thought to account for the observed myelin deficit. This study was undertaken to further define and quantify the specific lipid abnormalities that occur as a result of ASPA deficit in the tremor rat. Employing mass spectrometry together with high performance thin-layer chromatography, we found that myelin from 28-day-old animals showed major reduction in cerebrosides (CB) and sulfatides (Sulf) with unsubstituted fatty acids, and equal if not greater changes in myelin from 7-month-old tremors. Cerebrosides with 2-hydroxyfatty acids showed little if any change at either age; Sulf with 2-hydroxyfatty acids showed no significant change at 28 days, but surprisingly a major increase at 7 months. Two species of phosphatidylcholine, 32:0 and 34:1, also showed significant increase, but only at 28 days. One form of phosphatidylethanolamine, PE36:1, was reduced a modest amount at both ages, whereas the plasmalogen form did not change. The dysmyelination that results from inactivation of ASPA is thus characterized by selective decreases as well as some increases in specific lipids.

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Section: Introductionmentioning

confidence: 99%

Myelin Lipid Abnormalities in the Aspartoacylase-Deficient Tremor Rat

Wang

Leone

et al. 2008

Neurochem Res

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“…Seizure disorders or epilepsy syndromes are presently classified into Ͼ40 distinct types (Commission on Classification and Terminology of the International League Against Epilepsy, 1989). Although most epilepsies are considered to be multifactorial diseases, some specific types are considered single-gene disorders (Steinlein et al, 1995;Pennacchio et al, 1996;Biervert et al, 1998;Charlier et al, 1998;Fox et al, 1998;Singh et al, 1998;Wallace et al, 1998;McNamara, 1999).The tremor rat is a single-gene mutant found in the Kyoto:Wistar colony that exhibits absence-like seizure characterized by sudden immobility and staring, simultaneously with the appearance of 5-to 7-Hz spike-wave complexes in cortical and hippocampal EEG (Yamada et al, 1985;Serikawa et al, 1987;Hanaya et al, 1995). Homozygous rats (tm/tm) for the causative genetic locus tremor (tm) exhibit absence-like seizure after the age of 14 weeks, whereas heterozygotes (tm/ϩ) exhibit the same seizure less frequently after 26 weeks (Higashiguchi et al, 1991).…”

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Accumulation of N‐Acetyl‐L‐Aspartate in the Brain of the Tremor Rat, a Mutant Exhibiting Absence‐Like Seizure and Spongiform Degeneration in the Central Nervous System

Kitada

Akimitsu

Shigematsu

et al. 2000

Journal of Neurochemistry

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103

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Abstract:The tremor rat is a mutant that exhibits absence-like seizure and spongiform degeneration in the CNS. By positional cloning, a genomic deletion was found within the critical region in which the aspartoacylase gene is located. Accordingly, no aspartoacylase expression was detected in any of the tissues examined, and abnormal accumulation of N-acetyl-L-aspartate (NAA) was shown in the mutant brain, in correlation with the severity of the vacuole formation. Therefore, the tremor rat may be regarded as a suitable animal model of human Canavan disease, characterized by spongy leukodystrophy that is caused by aspartoacylase deficiency. Interestingly, direct injection of NAA into normal rat cerebroventricle induced 4-to 10-Hz polyspikes or spikewave-like complexes in cortical and hippocampal EEG, concomitantly with behavior characterized by sudden immobility and staring. These results suggested that accumulated NAA in the CNS would induce neuroexcitation and neurodegeneration directly or indirectly. Key Words: Tremor rats-Epilepsy-Neurodegeneration-Positional cloning-Aspartoacylase -N-Acetyl-L-aspartate. J. Neurochem. 74, 2512Neurochem. 74, -2519Neurochem. 74, (2000.Epilepsy is a diverse neurological abnormality that is characterized by recurrent seizures, affecting 1-2% of the population worldwide (McNamara, 1999). Epileptic seizures comprise alterations in sensory and motor systems and in consciousness. They result from the disordered, synchronous, and rhythmic firing of certain populations of neurons in the CNS. Current therapies are not satisfactory, as they do not provide symptomatic relief in some subsets of affected individuals and are sometimes accompanied by toxic effects. Elucidation of the cellular and molecular mechanisms underlying epileptogenesis, therefore, should lead to the development of new fundamental therapies and prevention methods, or even a cure. Seizure disorders or epilepsy syndromes are presently classified into Ͼ40 distinct types (Commission on Classification and Terminology of the International League Against Epilepsy, 1989). Although most epilepsies are considered to be multifactorial diseases, some specific types are considered single-gene disorders (Steinlein et al., 1995;Pennacchio et al., 1996;Biervert et al., 1998;Charlier et al., 1998;Fox et al., 1998;Singh et al., 1998;Wallace et al., 1998;McNamara, 1999).The tremor rat is a single-gene mutant found in the Kyoto:Wistar colony that exhibits absence-like seizure characterized by sudden immobility and staring, simultaneously with the appearance of 5-to 7-Hz spike-wave complexes in cortical and hippocampal EEG (Yamada et al., 1985;Serikawa et al., 1987;Hanaya et al., 1995). Homozygous rats (tm/tm) for the causative genetic locus tremor (tm) exhibit absence-like seizure after the age of 14 weeks, whereas heterozygotes (tm/ϩ) exhibit the same seizure less frequently after 26 weeks (Higashiguchi et al., 1991). In older age groups, wild running and jumping episodes are sometimes observed in tm/tm rats. However, spongiform degene...

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“…It occurs from about 4 weeks of age and is accompanied by wild jumping or running episodes after 12 months of age [14,19] . Zitter rats (zi/zi) have tremor in the hind body and tail after 2 weeks of age, which is associated with a progressive flaccid paresis with advance of age [101.…”

Section: Discussionmentioning

confidence: 99%

“…Mongolian gerbils also exhibit clonic-tonic seizures with motor arrest and myoclonic jerks of the body when placed in a new environment or given vestibular stimuli [71, but photic or auditory stimuli are not effective [2,5]. In genetically epilepsy-prone rats (GEPR) sound stimuli cause running episodes, clonus of hindlimbs' and tonic convulsion [4,11] Since the first report on zitter rats [101 and tremor rats [19], the characteristic neural symptoms in spontaneously epileptic rats (SER) and their original single homozygote rats have been studied extensively [12- Stimulation : To examine induction of seizure by touch, light and sound stimuli, rats were placed on the center of the bottom of a column (40 cm in diameter and 50 cm in height) with a light, an audiometer and a small window for a video-camera. Rats at 5, 9 and 13 weeks of age, were given the following stimuli after 15 min habituation.…”

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confidence: 99%