Hitoshi Nagara

The twitcher mouse: normal pattern of early myelination in the spinal cord

The pattern of early myelination was investigated in the dorsal columns of the cervical spinal cord in the twitcher, an authentic murine model of human globoid cell leukodystrophy, and their littermates. There were no differences in the number of myelinated fibers until the day 20 postnatal. However, myelin sheath in the homozygous affected twitchers at the day 20 were thinner than those of heterozygous and normal littermates, while at the day 10 no significant differences were detected. These observations indicated that in the twitcher mouse, despite the genetic deficiency of galactosylceramidase, myelination progresses normally in early stages and then hypomyelination becomes apparent before myelin breakdown.

An ultrastructural study on the cerebellum of the brindled mouse

SummaryChronological morphological alterations of the cerebellum, with particular attention to the Purkinje cells, were investigated in the brindled mottled MObr mouse, a neurological mutant mouse with close clinical similarity to Kinky hair syndrome (KHS) in humans. Seven days post-natally, slight irregularity in the morphology of mitochondria of the Purkinje cell perikarya was the only significant difference between hemizygous MObr mice and litter mate controls. With advancing age the mitochondrial change became more pronounced gradually in the former, not only in the perikarya but also in the dendrites. However, by day 31 or later the mitochondrial change subsided gradually and by day 91, the mitochondria in the majority of Purkinje cells became indistinguishable from those of littermate controls. Despite the extensive mitochondrial alteration, degeneration and necrosis of Purkinje cells were rather mild. Degeneration of white matter was quite conspicuous in the mutant mouse older than 31 days. These morphological changes of the cerebellum are compared with those of other neurological mutant mice, Nervous and Purkinje cell degeneration, and with KHS in humans.

The effect of copper supplementation on the brindled mouse: a clinico-pathological study.

Brindled mottled is a neurological mutant mouse. Hemizygous males have many clinical and biochemical features in common with kinky hair syndrome (KHS) in humans, and usually die around postnatal day 15, after severe emaciation. Neuronal mitochondrial abnormalities and neuronal degeneration in the cerebrum and cerebellum were constant neuropathological findings in this mutant. A single intraperitoneal injection of cupric chloride, 10 μg/g body weight, resulted in an improvement of clinical symptoms and prevention of neuronal degeneration. The degree of improvement was dependent on the date of injection, and day 7 or 10 postnatal appeared to be the most effective date. The male hemizygotes which received cupric chloride injections at day 7 or 10 overcame the lethality, and no neuronal degeneration was detected in these mice, although neuronal mitochondrial changes were still persistent. However, following two injections at days 7 and 10, no abnormalities were detected in the cerebral cortical neurons. Even at the ultrastructural level, abnormal mitochondria were very scarce. In the cerebellum, however, mitochondrial changes in the Purkinje cells, particularly in the rostral portion, and degeneration of white matter were noted in these mice, which were clinically perfectly healthy, judging from the growth rate and behavior. However, cerebellar changes were far less in those which received additional injections later on. These observations indicate that, at least in brindled mutant mice, supplementation of copper is quite beneficial for clinical improvement and the prevention of neuropathological lesions, but the date of administration appears to have crucial importance.

CHRONOLOGICAL STUDY OF OLIGODENDROGLIAL ALTERATIONS AND MYELINATION IN QUAKING MICE

Chronological morphological investigation was carried out in the spinal cord of quaking mice from day 3 to day 130. Numbers of myelinated fibres were far fewer in quaking mice at day 3 compared to controls. However, when the animals became older, myelination progressed and numbers of myelinated fibres increased although myelin sheaths remained far thinner than the size of axons. Many oligodendroglia during day 5 to 15 in quaking mice revealed prominent dilation and proliferation of smooth walled vesicles and cisterns but after 20 days, such changes were no longer observed. Tortuous bizarre oligodendroglial processes, aberrant myelination and myelin figures were very prominent around day 5–15, but such changes also gradually subsided. Density of glial cells during pre‐myelination gliosis was similar in both quaking and control mice. However, glial cell population decreased far slower pace than controls when myelination progressed. Thus, glial cell density remained proportionally higher in quaking than controls although the density declined with age in both.

Brindled mottled mouse: Morphological changes of brain and visceral organs in hemizygous males following copper supplementation

SummaryIntraperitoneal injections of cupric chloride prevent neuronal degeneration in the hemizygous brindled motled mouse, MObr/Y, a murine model of kinky hair syndrome (KHS) in humans. At 6–9 months after two i.p. injections, the brain of MObr/Y revealed slightly increased amounts of lipofuscin pigments in the cerebral cortical neurons, cytoplasmic inclusions in the thalamic neurons, and axonal spheroid formation in the tuber cinereum, cerebellum, and brain stem. Increased numbers of mitoses, bizarre hyperchromatic giant nuclei, and numerous clear vacuoles were frequently seen in the proximal renal tubular epithelium. Numerous myelin figures were conspicuous features in these epithelial cells at ultrastructural level. Such changes were not found in the littermate controls but in the heterozygous brindled mottled mouse, MObr/+, identical changes were noted in equal or even higher frequency. These observations suggest that cupric chloride injections effectively modify the expression of the genetic defect in MObr/Y.

Radial component of central myelin in shiverer mouse

Radial component of the central myelin was investigated in a neurological mutant mouse, shiverer, which is characterized by the lack of myelin basic protein and paucity of the major dense line in the CNS myelin. As has been noted previously in the normal as well as other neurological mutant mice, radial component consisted of rows of interlamellar tight junctions and was accompanied with electron lucent linear structures (ELLS) over the major dense lines. In the areas where major dense line had formed in shiverer CNS myelin, numerous ELLS run across the major dense lines and were not always associated with a fusion of double intraperiod lines. The possible role of ELLS in myelin formation is briefly discussed.

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.

RADIAL COMPONENT OF CENTRAL MYELIN IN NORMAL AND QUAKING MICE

Radial component of myelin sheaths was investigated in C57BL and quaking mice. In immature myelinated fibres of C57BL mice, more than one group of radial component were observed in the several regions of myelin sheaths while in mature fibres, one group of radial component was localized between the internal mesaxon and outer tongue process which were situated within 90° of each other. In thinly myelinated fibres of adult quaking mice, numerous groups of radial component were found at random distance and directions but they were always closely related to the cytoplasmic islands of oligodendroglia. Even in quaking mice, small well myelinated fibres showed normal mature pattern of radial component. Possible functional significance of radial component was briefly discussed.

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.

Quaking mouse: Vacuolar degeneration of spinal roots

SummaryQuaking 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.