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PubMed1987

Neuronal expression of mutations affecting primarily glia in the mouse: studies in the dysmyelinated and convulsive mutant quaking.

1. Various aspects of the noradrenergic system in the brain of the dysmyelinating convulsive mutant mice quaking have been examined. 2. Determination of the endogenous contents of noradrenaline and its metabolite 3-methoxy 4-hydroxyphenyl-ethyleneglycol (MOPEG), as well as measurement of the electrically-evoked release of (3H)-noradrenaline shows an increased noradrenergic activity in the brain of the mutants, when compared to non convulsive controls of the same strain. 3. Ontogenic development of alpha adrenergic receptors indicate that an increased density of alpha-2 sites precedes the appearance of the first convulsions by approximately one week. 4. Anatomical determination of the number of noradrenergic neuronal cell bodies in the locus coeruleus shows a hyperplasia of this nucleus in the mutants. 5. Electrolytic coagulation of the locus coeruleus inhibits the convulsions of the quaking mice. 6. These results suggest that an alteration of the embryonic differentiation of the locus coeruleus, which gives rise to the majority of brain noradrenergic neurons, provokes a hyperactivity of this neuronal system, thereby triggering the convulsions of the quaking mutant mice. 7. The possible involvement of other neurotransmitter systems in the convulsions of these mutants, together with the nature of the relationship between neuronal abnormalities and dysmyelination phenomenon, are discussed.

Animals↗
PubMed1982

Noradrenergic neurotransmission in the brain of a convulsive mutant mouse, differences between the cerebral cortex and the brain stem.

The Quaking mouse is a genetically determined model of convulsive disorders. We investigated the modulation of noradrenergic neurotransmission through alpha 2-adrenoceptors in the occipital cortex and the brain stem of this mutant. The endogenous levels of noradrenaline were similar in the cerebral cortex of the Quaking mice and their corresponding controls, while a significant increase of endogenous noradrenaline was found in the brain stem of the mutants. The rate of disappearance of noradrenaline in the cerebral cortex and the brain stem after injection of FLA 63 was identical in control and Quaking mice. The calcium-dependent electrically evoked overflow of 3H-noradrenaline from slices of occipital cortex was inhibited by clonidine and enhanced by yohimbine in Quaking as well as in normal mice. The negative feed-back mechanism mediated by presynaptic alpha 2-adrenoceptors operates to a similar extent in both strains of mice. In contrast to the occipital cortex, in the brain stem, the amount of neurotransmitter released by electrical stimulation was significantly increased in Quaking mice when compared with controls. However, in the brain stem, the negative feed-back regulation of noradrenaline release operates to a similar extent in both strains of mice. When the endogenous levels of MOPEG were determined in the brain stem, they were found to be significantly higher in the Quaking mice when compared to the controls. The results suggest that an increase in noradrenergic neurotransmission in the brain stem, rather than in the cerebral cortex, could contribute to the behavioural abnormalities exhibited by the Quaking mice.

Animals↗
PubMed1976

Copper supplementation in quaking mutant mice: reduced tremors and increased brain copper.

Mice homozygous for the mutant gene quaking (qk) with a high frequency of axial tremors had a low concentration of copper in the brain. Supplementation during pregnancy and lactation with a high level of dietary copper greatly reduced the frequency of tremors and brought brain copper level to normal in the off-spring. It is suggested that qk affects copper metabolism.

Animals↗
PubMed1977

Evidence for defective incorporation of proteins in myelin of the quaking mutant mouse.

The defect in myelinogenesis present in the Quaking mutant mouse was investigated using a double radioisotope technique for comparing the incorporation of amino acid into myelin proteins of normal and mutant mice. Quaking mice and littermate controls received intracranial injections of 150 muCi [3H]glycine and 25 muCi of [14C]glycine respectively. After 2 h their brains were combined and jointly processed to obtain subcellular fractions. The 3H/14C ratio for the myelin subfraction was 1.88 as compared to a 3H/14C ratio of 3.0 for the other subfractions, indicating a 40% decrease in glycine incorporation into myelin of Quaking mice. Myelin proteins were separated by discontinuous gel electrophoresis in the presence of sodium dodecyl sulfate (SDS) and the 3H/14C ratios determined in each gel slice. In contrast to the microsomal subfractions which gave a 3H/14C ratio of 2.6 across the gel, the 3H/14C ratio of myelin showed large variations with values ranging from 0.54 for proteolipid protein to 2.0 for some of the high molecular weight proteins. During development, the Quaking mutant exhibited a preferential depression in glycine incorporation into proteolipid protein in 18-day-old mice, while in older animals (32-54 days) the fast migrating basic protein, as well as the proteolipid protein, was labeled to a significantly lesser extent.

Age Factors↗
PubMed1981

Triethyl tin does not induce intramyelinic vacuoles in the cns of the quaking mouse.

Triethyl tin (TET), when injected intraperitoneally, failed to produce the typical intramyelinic edema in the spinal cord of quaking mice with two different genetic backgrounds (B6C3H-qk and BTBRTF/Nev-qk), while control littermates and normal C57BL/6J mice were susceptible, as expected. The only prominent change in the quaking mice was the presence of spherical vacuoles containing floccular electron-dense materials, some of which were clearly within the oligodendroglial perikarya and the inner and outer tongues. They are likely to represent degenerative responses. Consistent with the lack of edema, no increase in the water content was found in the quaking spinal cord following TET injection. Although the presence of numerous interlamellar tight junctions in quaking CNS myelin may mechanically restrict formation of the intralamellar vacuoles, the unique changes in the oligodendroglia and the lack of edema fluid accumulation suggest more fundamental metabolic abnormality that renders the quaking CNS resistant to the triethyl tin-induced edema.

Animals↗
PubMed1977

The differentiation of synthesis from incorporation of basic protein in Quaking mutant mouse myelin.

The incorporation of radioactive label into the myelin basic protein isolated from whole brain and from purified myelin of Quaking mice and normal littermates was compared. four Quaking mice (32 days) and 4 littermate controls were injected intracranially with 150 muCi [2-3H]glycine and 25 muCi of [2-14C]glycine, respectively. One hour later, the 8 mice were sacrificed and their brains combined for common homogenization. The 3H/14C ratios of the small and large basic protiens in whole brain were 3.44 and 2.48 respectively, while the 3H/14C ratios for these proteins in myelin were 0.79 and 1.00, respectively. In the same experiment, the microsomal fraction had a 3H/14C ratio of 2.98 which is the expected ratio for normal incorporation. The results indicate that the synthesis of basic protein in whole brain of Quaking mouse proceeds at a normal rate, but specifically, the incorporation of basic protein into myelin is depressed suggesting a defect at the step of assembly of myelin components into a final membrane product.

Animals↗
PubMed1977

Myelin consists of a continuum of particles of different density with varying lipid composition: major differences are found between normal mice and quaking mutants.

Mouse brain myelin consists of a continuum of particles of different densities, as shown by sucrose density gradient centrifugation. In normal animals most of the material (65 per cent) is concentrated between 0.6 and 0.7 M sucrose (the maximum being found at 0.66 M sucrose, corresponding to 23 per cent). The density differences among various myelin fractions are related to their protein/lipid ratios, as lighter fractions contain less protein and more lipid. Lipid analysis shows a decrease in the amount of every lipid from the lightest to the heaviest fraction: the light fraction is richer in phosphatidyl-ethanolamine, phosphatidyl-serine and cerebrosides. The distribution is highly abnormal in purified myelin from Quaking mutant ; very low quantities of myelin with normal density are found, but unexpected large amount of high density particles are found, possibly related to a "pre-myelin" material (oligodendrogial) processes which are not maturing into normal myelin).

Animals↗
PubMed1987

In vitro acylation of myelin PLP and DM-20 in the quaking mouse brain.

Both proteolipid proteins (PLP) and DM-20 were found to be present by the immunoblot technique in myelin isolated from quaking mouse brain; however, the relative concentration of these proteins in myelin from quaking brain was substantially reduced when compared to the control. Brain slices from littermate control and quaking mice were incubated with [3H]palmitic acid to determine the incorporation of fatty acid into myelin proteolipid proteins. Fluorography of gels containing myelin proteins from control and quaking mice brain revealed that both PLP and DM-20 were acylated. The incorporation of [3H]palmitic acid into quaking myelin PLP and DM-20 was reduced by 75% and 20% respectively of those in control brain. The significance of differential acylation of quaking myelin PLP and DM-20 is discussed with respect to availability of non-acylated pools of proteolipid proteins and the activities of acylating enzymes.

Acylation↗
PubMed1997

IL-6 and TNFalpha expression in brains of twitcher, quaking and normal mice.

Cytokines have been postulated to play a pathogenic role in twitcher mice, which are an animal model of globoid cell leukodystrophy. In particular, TNFalpha promotes oligodendrocyte and myelin pathology, and IL-6 expression is induced in astrocyte and microglial cultures that have been incubated with TNFalpha or myelin debris, respectively. It is unknown whether these cytokines are expressed in twitcher mice. The objectives of the present study were to develop an immunohistochemical method to detect TNFalpha and IL-6 in the mouse CNS, and then utilize this method to identify the cell types expressing these cytokines, and their spatial distribution, in the brains of normal, twitcher and quaking mice. In normal mice, IL-6 was found in ependymal cells, Bergmann glia, in processes that were adjacent or attached to the ventricles or pial surface, and in lightly stained processes in white matter. These processes were identified to belong to astrocytes and microglia. IL-6 staining was dramatically increased in twitcher mice. Astrocytes, with reactive features, and microglia were labeled in the cerebral cortex, basal ganglia, subcortical white matter, pons, medulla and cerebellar white matter. IL-6-positive reactive astrocytes were less abundant in quaking mice than twitcher mice. Cells expressing TNFalpha were rare or absent in normal and quaking mice. In twitcher mice, TNFalpha-positive macrophages were present at a lower concentration in cerebral white matter than in the pons and medulla, which have more advanced demyelination. These data demonstrate that pathological events induce the expressions of TNFalpha and IL-6 in the CNS of twitcher mice.

Animals↗
PubMed1991

The quaking mouse: an epileptic mutant with alterations affecting the modulatory mechanisms of the NMDA receptor complex.

The binding of [3H]glutamate and of [3H]1-(1-(2-thienyl)cyclohexyl)piperidine [( 3H]TCP) has been examined in the genetically epileptic mutant mouse, quaking. The density of [3H]glutamate binding sites did not differ between the quaking mice and their controls of the same strain. In the absence of exogenous glutamate or glycine, the density of [3H]TCP binding sites was also similar in the two strains. In both the mutants and their controls, exogenously added glutamate, glycine and glutamate plus glycine dose-dependently increased the binding of [3H]TCP. In the 3 conditions, the modulation of [3H]TCP binding was significantly more efficient in the quaking mice than in the controls. Furthermore, in the presence of glutamate (10(-5) M), the increase of the affinity of the ligand for the ion channel binding site was higher in the mutants than in the controls. These results suggest that the modulatory mechanisms of the N-methyl-D-aspartate/ionophore receptor complex might be altered in these mutants. These alterations might be related to the previously observed anticonvulsant properties of NMDA receptor antagonists in the quaking mouse model of inherited epilepsy.

Animals↗
PubMed1989

Myelin-associated glycoprotein (MAG) and rat brain-specific 1B236 protein: mapping of epitopes and demonstration of immunological identity.

The myelin-associated glycoprotein (MAG) and the brain 1B236 protein are 100-kDa glycoproteins containing 30% carbohydrate that exist in two developmentally regulated forms and are specific to the nervous system. Recent cDNA cloning experiments in several laboratories using primarily immunological means of identification have determined the complete primary sequence of a rat brain glycoprotein that seems to correspond to both MAG and 1B236, suggesting that these proteins are identical. However, MAG was previously considered to be an oligodendrocyte/myelin specific component in the CNS at all ages, whereas 1B236 was thought to be primarily a neuronal component in adult rats but synthesized by oligodendrocytes at the time of active myelination. The composite term 1B236/MAG was proposed to describe the molecule identified by the cDNAs. In order to explore further the relationship between MAG and 1B236, as well as their developmentally regulated forms, experiments were carried out on rat samples utilizing synthetic peptides corresponding to sequences throughout the 1B236 molecule, antisera raised to synthetic peptides in the C-terminus of 1B236 that distinguish between the two developmentally regulated forms, and well-characterized polyclonal and monoclonal antibodies raised to purified MAG. Epitope mapping demonstrated that reactive sites were distributed throughout the extracellular and intracellular domains of 1B236/MAG. Only antibodies reacting with the smaller of the two forms of 1B236/MAG detected the glycoprotein in the peripheral nervous system. Both anti-MAG and anti-1B236 antibodies revealed a drastic reduction of the level of 1B236/MAG in 25-day-old myelin-deficient rats and in adult quaking mice, and both types of antibodies revealed a slight shift of 1B236/MAG toward higher apparent Mr in quaking mice as had previously been reported for MAG. The results indicate that MAG and 1B236 are almost certainly identical since they cannot be distinguished immunologically by the reagents available and that quantitatively most of the glycoprotein is associated with oligodendrocytes and myelin rather than neurons at all ages.

Animals↗
PubMed1978

Proteins from sciatic-nerve myelin in quaking and jimpy mice.

Myelin from two neurological mutants in mice was isolated from sciatic nerves and its protein composition analysed. In Quaking mice, two intrinsic myelin proteins P1 and P2 were drastically decreased, whereas the major myelin protein P0 was unaffected. A normal protein composition was found in sciatic myelin from Jimpy mice.

Animals↗
PubMed1985

Brain gangliosides of quaking and shiverer mutants: qualitative and quantitative changes of monosialogangliosides in the quaking brain.

Ganglioside compositions in the brains of the mutant mice quaking and shiverer were compared with those of their littermate controls, C57BL/6 and C3HSWV. Neither ganglioside content nor composition of shiverer brains differed from those of the control brains. Change in the ganglioside composition of the mutant brain from that of the control was observed only in the quaking mutant brain, in which monosialoganglioside GM1 was significantly reduced and GM4 was completely absent. The structures of the gangliosides were determined by negative ion fast atom bombardment mass spectrometry, and the GM3 and GM4 gangliosides in the quaking brain were found to be altered in regard to their long-chain base and fatty acid compositions when compared to the normal C57BL/6 brain.

Animals↗
PubMed1985

Altered postnatal ontogeny of alpha 1- and alpha 2-adrenoceptor binding sites in the brain of a convulsive mutant mouse (quaking).

Binding assays of [3H]dihydroalprenolol ([3H]DHA), [3H]prazosin and [3H]clonidine have been performed on whole brain (minus cerebellum) homogenates of the convulsive mutant mice quaking (qk) and the controls of the same strain (C57BL/6J:B6). In 70-day-old mutants (which fully exhibit the qk convulsive phenotype), the binding of [3H]DHA to beta-adrenoceptor binding sites was not different from the controls, whereas the binding capacities of [3H]prazosin and [3H]clonidine to alpha 1-and alpha 2-adrenoceptor sites, respectively, were greatly enhanced. The biphasic ontogenic pattern of alpha 2-adrenoceptors had a greater amplitude in the brain of 30- to 90-day-old mutants than in the corresponding B6 controls. In mutants younger than 30 days or older than 90 days, the number of alpha 2-adrenoceptor sites was not modified. The number of alpha 1-adrenoceptor binding sites was increased in the brain of the mutants, only in animals older than 70 days. In younger mice, the postnatal modulation of alpha 1-adrenoceptor sites was identical to the controls. Regional studies were performed in 70-day-old mice. [3H]clonidine binding was increased in the brainstem of the mutants, and to a lesser extent in the cerebral cortex, while it was slightly diminished in the hypothalamic area. [3H]prazosin binding was also increased in the brainstem of the mutants, and decreased in the olfactory bulbs. Our results suggest that the convulsions of the qk mutants are selectively associated with modifications of alpha- and not beta-adrenoceptor binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Studies on myelin basic protein-specific protein methylase I in various dysmyelinating mutant mice.

Jimpy mice are dysmyelinating mutants characterized by producing near normal levels of myelin basic protein (MBP) in the brain but failing to incorporate these proteins into the myelin sheath. In this study, the activity of MBP-specific protein-arginine N-methyltransferase (protein methylase I) was studied in the brains of normal and jimpy mice of different ages. The enzyme activity varied little with age in normal mice but in 18 and 21 days-old homozygous jimpy mice the activity was reduced by 50% and 75% respectively from the level of their normal littermates. Interestingly, however, heterozygous jimpy mice who are phenotypically normal and quaking mice (a similar dysmyelinating mutant) showed unaltered enzyme levels.

Age Factors↗
PubMed1981

Resistance of quaking mouse CNS to triethyl tin edema.

Intraperitoneal injection of triethyl tin (TET) sulfate, 5 or 10 mg/kg body weight did not induce intramyelinic edema without altering water content in quaking mice while in C57BL/6J and littermate control mice, water content was increased and typical intramyelinic edema was induced following TET injection. Even among control mice, however, there were some strain differences in the histological severity of the edema, which were in precise agreement with the quantitative alterations in water content. These observations suggest that CNS myelin in quaking may differ qualitatively from that in controls and the mode of response to TET is under genetic control.

Animals↗
PubMed1981

[Free and sulfo-conjugated dehydroepiandrosterone in the brain of mice with myelin biosynthesis disorders].

Dehydroepiandrosterone, either unconjugated (D) or conjugated to sulfuric acid (DS), has been identified in the brain of male Mice; DS had been previously found in Rat brain. DS amounts in posterior brain, were 0.8-2.0 ng/g in controls, and very much lower in dysmyelinic jimpy and quaking Mice of the same age. Conversely, amounts of D were increased in affected Mice, suggesting an impaired sulfoconjugation. Results may be explained by accumulation of D and DS in brain, unrelated to the endocrine system.

Animals↗