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PubMed1995

Dopaminergic brain system in the quaking mutant mouse.

Quaking mice (qk/qk), autosomal recessive mutants with central nervous system dysmyelinization, characterized behaviorally by abnormal locomotion and tremor, are found to have altered brain dopaminergic system parameters, in comparison with phenotypically normal heterozygous littermates. Dopamine metabolism is enhanced in structures of both nigrostriatal and mesolimbic systems, as revealed by increased metabolites content (that of homovanillic acid in striatum and concentration of 3,4-dihydroxy-phenylacetic acid in nucleus accumbens with tuberculum olfactorium) along with unchanged neurotransmitter levels in qk/qk mice. D1 and D2 receptor analysis via radioligand binding using [3H]-SCH 23390 and [3H]-spiperone, correspondingly, showed an increase of D2 receptor density with decreased affinity to D2 ligand in striatum of mutants: both Bmax and Kd were markedly higher. D1 and D2 receptor sensitivity in the quaking mouse was also altered. Stimulation of D1 receptors by a highly specific agonist SKF 38393 (2.5 and 5 mg/kg) decreased locomotor activity only in mutants, but not in controls. In contrast, qk/qk were less sensitive than phenotypically normal qk/+ mice to a selective D2 dopamine receptor agonist, LY 171555 (quinpirole, 1 and 2.5 mg/kg). The alterations found in the brain dopaminergic system of qk/qk mice may be responsible for the behavioral expression of this neurologic mutation.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1982

Quaking mouse: vacuolar degeneration of spinal roots.

Quaking is a neurologic mutant mouse with hypomyelination of CNS and PNS. In this mutant mouse of over 6 months of age, extensive vacuolation was found in the nerve fibers of the spinal roots, mostly in the ventral root. Normal axoplasmic constituents, such as mitochondria, neurotubules, and neurofilaments were, in general, well preserved. Many of these vacuoles appeared to be intra-axonal and only a few showed direct continuity with dilated periaxonal space. However, moderately electron-dense fluffy materials were often found in both the vacuoles and in the dilated periaxonal space, and rare mononuclear cells were found within the vacuoles, suggesting that these vacuoles were likely to be dilated periaxonal spaces. The vacuoles tended to be found more often in the myelinated nerve fibers than non-myelinated fibers. The changes in the periaxonal spaces observed in the old quaking mice were closely similar to those found in the myelinated cultures maintained on low calcium medium (Blank et al. 1974). Since calcium is highly concentrated in the node-paranodal regions and may be involved in the adhesion of Schwann cell loops to the axolemma (Ellisman et al. 1979), disturbed calcium and possibly other ionic concentrations due to structural abnormalities of node and paranodal regions in quaking mouse (Suzuki and Zagoren 1977) are speculated to be responsible for such morphological changes of spinal root in this mutant mouse.

Age Factors↗

PubMed1988

Distribution of the myelin-associated glycoprotein and P0 protein during myelin compaction in quaking mouse peripheral nerve.

Ultrastructural studies have shown that during early stages of Schwann cell myelination mesaxon membranes are converted to compact myelin lamellae. The distinct changes that occur in the spacing of these Schwann cell membranes are likely to be mediated by the redistribution of (a) the myelin-associated glycoprotein, a major structural protein of mesaxon membranes; and (b) P0 protein, the major structural protein of compact myelin. To test this hypothesis, the immunocytochemical distribution of these two proteins was determined in serial 1-micron-thick Epon sections of ventral roots from quaking mice and compared to the ultrastructure of identical areas in an adjacent thin section. Ventral roots of this hypomyelinating mouse mutant were studied because many fibers have a deficit in converting mesaxon membranes to compact myelin. The results indicated that conversion of mesaxon membranes to compact myelin involves the insertion of P0 protein into and the removal of the myelin-associated glycoprotein from mesaxon membranes. The failure of some quaking mouse Schwann cells to form compact myelin appears to result from an inability to remove the myelin-associated glycoprotein from their mesaxon membranes.

Animals↗

PubMed1990

Anticonvulsant effects of antagonists of the N-methyl-D-aspartate receptor complex in a genetic model of epilepsy: the quaking mouse.

Tonic-clonic convulsions of mutant quaking mice were antagonized by the intracerebroventricular injection of N-methyl-D-aspartate receptor antagonists. The competitive antagonists, CPP (3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid) and CGS 19755 (cis-4-(phosphonomethyl)-2-piperidine carboxylic acid), exerted a partial anticonvulsant action, with ED50S of 0.115 and 0.076 nmol, respectively. The non-competitive antagonists, TCP (1-(1-(2-thienyl)cyclohexyl)piperidine) and MK-801 [+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine), provided full protection, with ED50s of 4.49 and 2.67 nmol, respectively. The competitive antagonists elicited a marked ataxia whereas the non-competitive antagonists did not have side-effects. These results might reflect the involvement of glutamatergic neurotransmission in the convulsions of the quaking mutants.

Animals↗

PubMed1996

Order-disorder phenomena in myelinated nerve sheaths. VI. The effects of quaking, jimpy and shiverer mutations: an X-ray scattering study of mouse sciatic and optic nerves.

We report the X-ray scattering study of sciatic and optic nerve myelin from shiverer, jimpy and quaking mice mutants and from the corresponding controls. These three mutations are known to affect dramatically central nervous system (CNS) myelin and to induce comparatively minor alterations in peripheral nervous system (PNS) myelin. Scattering experiments and data reduction were carried out using the techniques and algorithms developed in our laboratory and previously applied to several problems involving the structure of myelin. In sciatic nerve the fraction of myelin elementary pairs of membranes (total myelin) decreases in shiverer and quaking nerves (by approximately 30%) but not in jimpy nerves; in all three mutants the fraction of myelin membrane pairs that are not regularly stacked in the sheaths (loose myelin), the average number of membranes per sheath and the packing disorder are the same as in the control nerves; the repeat distance D and the membrane distance Dcyt across the cytoplasmic space increase in shiverer and decrease in jimpy; in quaking, D also decreases and the decrease is smaller than in jimpy and is not specific for Dcyt; small changes are also observed in the electron density profiles. As for the optic nerve the myelin content decreases dramatically in the three mutants; the very weak signal attests to a tiny amount of pairs of membranes structurally similar to normal CNS myelin. It is surprising that the structure of CNS myelin should be almost normal in the absence of the major structural components, namely myelin basic protein (MBP) for shiverer of proteolipid protein (PLP) for jimpy. The question arises whether the composition of the residual pairs of membranes, operationally identified as myelin in the X-ray scattering experiments, mirrors the composition determined by chemical means on the fraction of nerve tissue histologically identified as myelin, or whether in all circumstances it remains approximately the same.

Animals↗

PubMed1991

Oligodendrocytes and myelin sheaths in normal, quaking and shiverer brains are enriched in iron.

Early studies employing iron histochemical techniques found a spatially restricted distribution of oligodendrocytes and myelin enriched in iron. In particular, oligodendrocytes and myelin positively stained for iron were found in sparsely myelinated brain regions but not in densely myelinated tracts. Subsequent studies modified the iron histochemical technique and demonstrated that oligodendrocytes and myelin were stained in densely myelinated brain regions but the staining occurred in patches rather than uniformly throughout densely myelinated tracts. This study further modified the iron histochemistry technique to establish that oligodendrocytes and myelin are enriched in iron throughout densely myelinated tracts. This finding supports biochemical studies that detected high levels of iron in white matter (Hallgren and Sourander, J Neurochem 3:41-51, 1958) and myelin fractions of brain homogenates (Rajan et al., Life Sci 18:423-432, 1976). Thus, this histochemical study and earlier biochemical studies indicate that white matter is a major site of iron concentration within the brain. The present study also examined the distribution of iron in oligodendrocytes and myelin from the dysmyelinating mutant mice quaking and shiverer. Results from these studies demonstrate that oligodendrocytes and myelin are enriched in iron in both quaking and shiverer brains. An unexpected finding was an intense staining of oval structures within the oligodendrocyte cytoplasm. This result indicates a concentration of iron in these structures and may be important for understanding how high concentrations of iron are processed by oligodendrocytes.

Animals↗

PubMed1989

Glial hyaluronate-binding protein in dysmyelinating mice mutants: jimpy, quaking and shiverer.

Cryostat sections of cerebral hemispheres, cerebellum and spinal cord from dysmyelinating mice mutants (quaking, jimpy and shiverer) and littermate controls were stained by indirect immunofluorescence with polyclonal antibodies to the glial hyaluronate-binding protein (GHAP), a brain-specific extracellular matrix glycoprotein produced by astrocytes. In normal mice, the distribution of GHAP was similar to that previously reported in human, calf, pig and dog. The antigen was mainly localized in white matter, the granular layer of the cerebellum being the main exception. No differences were observed between mutants and littermate controls, except that with both GHAP and glial fibrillary acidic protein antibodies the glial framework was denser in the mutants, probably due to the reduction in myelin. The findings suggest that GHAP expression by astrocytes is not induced by myelination and that white matter astrocytes constitute a distinct glial population.

Animals↗

PubMed1977

Myelin subfractions isolated from mouse brain. Studies of normal mice during development, quaking mutants, and three brain regions.

Myelin isolated from three areas of mouse brain, from whole brain at several ages in normal mice, and from whole brain of adult quaking mutant mice was separated into seven bands and a pellet on discontinuous density gradients using 0.32, 0.45, 0.55, 0.60, 0.70, 0.75 and 0.85 M sucrose. The distribution of myelin in the subfractions was independent of homogenization and shocking conditions employed to isolate the myelin preparations, but was related to the type of myelin applied to the gradient. Compared to myelin isolated from older animals, myelin isolated from 18-24 day old mice displayed a distribution pattern with greater proportions of material banding at lesser sucrose densities. Similarly, myelin obtained from hindbrain contained proportionately more material layering at lesser sucrose densities compared to myelin isolated from cerebral cortex. Myelin subfraction patterns observed for 8-12 day old control mice and quaking mutants were unlike each other or any other myelin preparation examined. In the 18-90 days old animals, the markers studied were not uniformly distributed among the myelin subfractions. The pellet and the layer banding at the 0.75/0.85 M sucrose interface contained the highest specific concentrations of sialic acid, nucleic acid, and total adenosine triphosphatase activity. In contrast, the specific activity of 2',3'-cyclicnucleotide-3'-phosphohydrolase was lowest in the pellet as well as the three bands obtained above 0.60 M sucrose and was highest in the fraction banding at the 0.65/0.70 M sucrose interface. The results obtained were not consistent with an artifactual origin of the myelin subfractions, but instead suggested that the subfraction have physiological significance. One explanation for the different banding patterns observed between young and mature myelin may be the different amount of myelin in various brain regions during development.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗

PubMed1980

Immunohistochemical localization of the myelin basic protein and of the glial fibrillary acidic protein: comparative study in normal, quaking and jimpy mice.

The topographical distribution of myelin basic protein (MBP) and of glial fibrillary acidic protein (GFA) have been compared in the CNS of 18-day-old normal, quaking, and jimpy mice using indirect immunofluorescence. Comparison was made in brain and spinal cord sections. MBP was strongly decreased in quaking and jimpy mice in all parts of the CNS. A pronounced gliosis was observed in jimpy mice with occurrence of numerous hypertrophied astrocytes. To a lesser extent, an astrocytic reaction was also observed in quaking CNS.

Animals↗

PubMed1982

Increased axonal proteolysis in myelin-deficient mutant mice.

Protein degradation within retinal ganglion cell axons in vitro is 50 to 110 percent faster than normal in mutant mice exhibiting deficiencies of myelin in the central nervous system. Proteolysis is increased proximally and distally within retinal ganglion cell axons of mice carrying the jumpy mutation or its allele, myelin synthesis deficiency, and is increased distally within those axons of quaking mice. The proteolytic defect is axon (neuron)-specific since the rate of protein degradation within glial cells is normal. Increased axonal proteolysis does not bear a simple relation to hypomyelination since shiverer, another mouse mutant deficient in central myelin, displayed normal rates of axonal protein degradation under the same conditions. These observations suggest an abnormal axon-glial interaction in mice with primary glial defects and raise the possibility that the functioning of histologically normal axons (neurons) may be altered in dysmyelinating diseases.

Animals↗

PubMed1984

Murine leukodystrophies as tools to study myelinogenesis in normal and pathological conditions.

Myelinogenesis is controlled by several genes. Therefore, the study of mutations affecting myelination should provide better understanding of the assembly and maintenance of myelin, and in the case of similitude with human diseases, a direct insight into the pathogenesis of these diseases. Murine mutants can be bred readily and sequential analyses allow an examination of the dynamic processes of myelination. In this study, we have selected certain aspects of four leukodystrophies in mice. The precise mechanisms leading to the important myelin deficit observed in the jimpy mutation, a sex-linked recessive trait, are still not completely elucidated. Our results show in jimpy mice severe astrocytic alterations prior to myelin formation. Therefore, abnormalities of oligodendrocytes and possibly axons could be a secondary phenomenon. Nevertheless, a defect involving neuroglia precursor cells cannot be ruled out. At the present time, Pelizaeus-Merzbacher is a disease in which mainly oligodendrocytes appear to be altered. In consequence, our findings in jimpy mice do not support the present contention that this mutation represents a model for Pelizaeus-Merzbacher disease. We propose that the jimpy mutation could be invaluable to study cell-cell interactions at an early stage of myelinogenesis. Interest in the myelin deficient (mld) mutant derives from the specific lack of one of the major myelin constituents, myelin basic protein, and the concomitant absence of the major electron dense line during the active phase of myelin deposition in the CNS. Our present knowledge points out a defect of gene regulation involving myelin basic protein synthesis. The absence of this extrinsic membrane component made it possible to catch a glimpse of its role in the formation and maintenance of the complex structure of the myelin sheath in the CNS. Quaking mice have been considered to represent an arrest of myelinogenesis. This commonly accepted view has to be reconsidered at the light of recent morphological and biochemical findings. An abnormal processing of the myelin-associated glycoprotein could prevent the normal compaction of myelin until the animals reach adulthood. Twitcher is characterized by extensive central and peripheral demyelination and the presence of intracellular inclusions in macrophages similar to human globoid cell leukodystrophy. In both human and murine diseases, a deficiency of galactosylceramidase activity was demonstrated.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1970

Cerebral acid hydrolase activities: comparison in "quaking" and normal mice.

The activity of several acid hydrolase enzymes was determined in whole brain homogenates of adult "quaking" and normal mice. A striking decrease was found in alpha-mannosidase and, to a lesser extent, aryl sulfatase levels in the samples from the mutant animals. The activities of the other "lyso-somal" enzymes were only slightly lowered.

Animals↗

PubMed1977

Quaking mouse: an ultrastructural study of the peripheral nerves.

Ultrastructural study of the peripheral nervous system of quaking mice has revealed several unusual features in the pattern of myelination in addition to hypomyelination. These are 1) the presence of 'atypical' Schmidt-Lanterman incisures, 2) irregularities of the nodal and internodal termination of Schwann cell cytoplasm and 3) the presence of non-myelinated segments without associated Schwann cell processes, but covered by basal lamina. In view of the observation of similar features during the development of the P.N.S. and also during P.N.S. remyelination, we suggest that these features are the results of modified myelination due to a defect in the control mechanisms necessary for normal myelination.

Animals↗

PubMed1989

Age-dependent supersensitivity to the glycogenolytic effect of K+ in the cerebral cortex of the spontaneously epileptic quaking mouse mutant.

K+, at concentrations reached in the extracellular space during neuronal activity (5-10 mM), promotes a time- and concentration-dependent hydrolysis of [3H]glycogen newly synthesized by mouse cerebral cortical slices. In the present study, the glycogenolytic action of K+ was examined in the neocortex of the quaking mouse, a spontaneously epileptic mutant characterized by deficient myelination of the CNS. The potency and efficacy of K+ in eliciting glycogen hydrolysis was greatly enhanced in cerebral cortical slices prepared from homozygous quaking mice (qk/qk) older than 7 weeks of age, indicating a supersensitive response to a metabolic action of the ion. A detailed ontogenic analysis showed an evolution of the supersensitive response to K+ which is reminiscent of the previously described increase in the number of alpha 2-adrenoreceptors in the brainstem of this mutant. In contrast to the altered response to K+, the glycogenolytic action of noradrenaline and vasoactive intestinal peptide reported earlier was equally expressed in qk/qk and in their unaffected littermates.

Aging↗

PubMed1994

Nervonic acid and demyelinating disease.

Demyelination in adrenoleukodystrophy (ALD) is associated with an accumulation of very long chain saturated fatty acids such as 26:0 stemming from a genetic defect in the peroxisomal beta oxidation system responsible for the chain shortening of these fatty acids. Long chain monoenoic acids such as erucic acid, 22:1(n-9), can normalise elevated serum levels of 26:0 in ALD by depressing their biosynthesis from shorter chain saturated fatty acids. Sphingolipids from post mortem ALD brain have decreased levels of nervonic acid, 24:1(n-9), and increased levels of stearic acid, 18:0. Increased levels of 26:0 are accompanied by decreased nervonic acid biosynthesis in skin fibroblasts from ALD patients. Sphingolipids from post mortem MS brain have the same decreased 24:1(n-9) and increased 18:0 seen in post mortem ALD brain. The 24:1(n-9) content of sphingomyelin is depressed in erythrocytes from multiple sclerosis (MS) patients. Defects in the microsomal biosynthesis of very long chain fatty acids including 24:1(n-9) in 'jumpy' and 'quaking' mice are accompanied by impaired myelination. An impairment in the provision of nervonic acid in demyelinating diseases is indicated, suggesting that dietary therapy with oils rich in very long chain monenoic acid fatty acids may be beneficial in such conditions.

Adrenoleukodystrophy↗

PubMed1989

The fetal hydantoin syndrome: answers from a mouse model.

In spite of a large body of literature suggesting that prenatal exposure to hydantoin anticonvulsant drugs can be teratogenic in humans, resulting in offspring with congenital malformations, the wide phenotypic variability of this syndrome has led many clinicians to question its very existence. Because solutions to major teratologic questions may be impossible to find within the constraints of human clinical or epidemiologic investigations, we have developed an animal model for the fetal hydantoin syndrome. With this model, we have been able to demonstrate the dose-related teratogenic effects of phenytoin on mouse development and the positive correlation between increasing maternal plasma phenytoin concentrations and the risk for congenital anomalies among offspring. Further, we have shown that genetic differences in susceptibility to particular phenytoin-induced malformations exist within different inbred mouse strains. Finally, in homozygous quaking (qk/qk) mice, the fetal malformations were associated not with the presence of a maternal seizure disorder, but with the phenytoin treatment of the disorder. An animal model such as the one described in this paper serves as a valuable adjunct to human clinical studies, and may serve to shorten the distance between our current understanding and our goal of preventing preventable birth defects.

Abnormalities, Drug-Induced↗

PubMed2006

Rescuing qkV dysmyelination by a single isoform of the selective RNA-binding protein QKI.

Alternative splicing of the qkI transcript generates multiple isoforms of the selective RNA-binding protein QKI, which play key roles in controlling the homeostasis of their mRNA targets. QKI deficiency in oligodendrocytes of homozygous quakingviable (qkV/qkV) mutant mice results in severe hypomyelination, indicating the essential function of QKI in myelinogenesis. However, the molecular mechanisms by which QKI controls myelination remain elusive. We report here that QKI-6 is the most abundant isoform in brain and is preferentially reduced in the qkV/qkV mutant during normal myelinogenesis. To test whether QKI-6 is the predominant isoform responsible for advancing CNS myelination, we developed transgenic mice that express Flag-QKI-6 specifically in the oligodendroglia lineage, driven by the proteolipid protein (PLP) promoter. When introduced into the qkV/qkV mutant, the QKI-6 transgene rescues the severe tremor and hypomyelination phenotype. Electron microscopic studies further revealed that the Flag-QKI-6 transgene is sufficient for restoring compact myelin formation with normal lamellar periodicity and thickness. Interestingly, Flag-QKI-6 preferentially associates with the mRNA encoding the myelin basic protein (MBP) and rescues MBP expression from the beginning of myelinogenesis. In contrast, Flag-QKI-6 binds the PLP mRNA with lower efficiency and has a minimal impact on PLP expression until much later, when the expression level of QKI-6 in the transgenic animal significantly exceeds what is needed for normal myelination. Together, our results demonstrate that QKI-6 is the major isoform responsible for CNS myelination, which preferentially promotes MBP expression in oligodendrocytes.

Animals↗

PubMed1982

[Genetic and cytogenetic marking of the neurological quaking mutation (qk) in laboratory mice].

A new genetically balanced breeding system with a low recombination rate is offered for purposes of maintenance and early identification of mice with the recessive autosomal qk mutation. Dominant T mutation (Brachyury) and recessive t12 mutation of T locus were chosen as genetical markers and Robertsonian translocation Rb (8.17) 1 Iem served as a cytogenetical marker of the qk mutation. As shown by the results, none of genetical mutations studied (qk, T or t12) can be distinguished on differentially stained chromosomal preparations. Hybrid mice of the +T/qk+ genetic compound have a high rate (44%) of homozygous qk/qk offspring. The latter can be identified with the high probability (96%) in foetuses and newborns, according to their tail length, well before the typical neurological symptoms are evident. In the offspring of the F1 hybrids+Rb 1 Iem/qk+ the frequency of qk/qk mice is near 20% and they can be identified with the probability 95% at any stage of the development by means of chromosomal analysis. Hybrids of the +t12/qk genotype are very convenient for prolonged maintenance of the qk gene in a balanced heterozygous condition. Some features of functional similarities between the qk gene and recessive mutations of T locus are discussed. Genetical and cytogenetical markers used in this work provide some novel approaches for experimental analysis of the qk gene expression at early stages of the development.

Animals↗