Development of myelin mosaicism in the optic nerve of heterozygotes of the X-linked myelin-deficient (md) rat mutant.

The oligodendrocyte population of the optic nerve has been suggested to arise either from a radial migration of neuroepithelial cells of the optic stalk or from the longitudinal migration of progenitor cells into the optic nerve from the brain, via the optic chiasm. Female heterozygotes of the X-linked myelin deficient (md) rat trait show a marked mosaic pattern of myelination of the optic nerves. This degree of mosaicism is not observed in other parts of the central nervous system. A total of 235 optic nerves from female rats of from 3 weeks to 24 months of age were examined by light microscopy. Nerves (104), from rats of all ages, showed defects in myelination consisting of distinct patches of non-myelination, often sharply demarcated from adjacent areas of normally myelinated axons. In some animals the abnormality was grossly apparent as areas of transparency within the intact optic nerves. In the majority of optic nerves showing mosaicism, defects in myelination were observed along the whole length of the nerve. However, a worsening of the defect toward the retinal end of the nerve was noted in 15 optic nerves, and an additional 11 nerves showed a defect in this region alone. It was also found that a number of rats had mosaicism in only one optic nerve. The preferential involvement of the retinal end of the optic nerves, and the asymmetrical involvement of the optic nerves within individual rats, is interpreted as indirect evidence in support of the proposed longitudinal migration of the oligodendrocyte precursor into the optic nerve.

Preferential denervation of the adductor muscles of the equine larynx. I: Muscle pathology.

The laryngeal muscles of 18 horses were examined histologically. The neurogenic changes found in each muscle were scored by four reviewers and the results evaluated statistically. Fifteen of these horses had endoscopic evidence of abnormal laryngeal function, three of which were defined as having adductor paralysis. Measurement of muscle fibre area in two horses with idiopathic laryngeal hemiplegia (ILH) was performed. In the quantitative study of neurogenic change, the adductor muscles were more significantly affected than the abductor muscle. This was also true in the clinical cases of ILH where measurement of muscle fibre area demonstrated that the lateral cricoarytenoid (adductor) muscles showed a wider range of pathological changes than the dorsal cricoarytenoid muscle (abductor). Those horses with the most severe muscle pathology also had the most abnormal endoscopic findings. The propensity for denervation of the adductor muscles should provide clues as to the pathogenesis and natural history of horses with sub-clinical laryngeal disease and ILH.

Preferential denervation of the adductor muscles of the equine larynx. II: Nerve pathology.

The terminal branches of the recurrent laryngeal nerve (RLN) of three normal ponies and six horses with sub-clinical laryngeal disease were examined qualitatively and quantitatively in an attempt to explain the preferential denervation of the laryngeal adductor muscles in the neuropathy of idiopathic laryngeal hemiplegia (ILH). The myelinated fibre spectra of all the motor nerve fibres in the left and right abductor and adductor branches of the RLN in three normal ponies were measured. The density of myelinated fibres was also calculated. There was no significant difference between the larger group of myelinated fibres in the adductor or abductor branches. In the six horses with laryngeal hemiparesis, however, there was a marked preferential loss of the medium/large size myelinated fibres in the left adductor branch, although nerve fibre densities were not significantly different. While no simple morphometrical feature was found to explain the selective muscle denervation, the greater loss of large diameter myelinated fibres in the adductor branches confirms the earlier observation of adductor muscle susceptibility in the neuropathy of ILH.

Hypomyelination in the neonatal rat central and peripheral nervous systems following tellurium intoxication.

Neonatal rats were exposed to Tellurium (Te), via the mother's milk, from the day of birth until sacrifice at 7, 14, 21, and 28 days of age. Light and electron microscopy revealed Schwann cell and myelin degeneration in the sciatic nerves at each age studied. These changes were similar to those described in weanling rats as a result of Te intoxication. In the CNS, hypomyelination of the optic nerves was convincingly demonstrated at 14, 21, and 28 days of age, accompanied by some evidence of myelin degeneration. These changes were also seen in the ventral columns of the cervical spinal cords, although less markedly, and were confirmed by quantitative methods. There was little evidence of oligodendrocyte pathology in the CNS, and it appears that degeneration of these cells is not the primary cause of the CNS hypomyelination, in contrast to the PNS where Schwann cell degeneration has been shown to precede the myelin pathology.

Cell kinetics and cell death in the optic nerve of the myelin deficient rat.

The optic nerves of myelin deficient (md) and normal rats were studied by light microscopic thymidine autoradiography and electron microscopy during the first postnatal month. Mean total glial cell counts were similar at most ages in the md and normal optic nerves, but were significantly increased in the md nerves at 18 days of age, and significantly reduced at 30 days, compared to the controls. Labelling indices in the md optic nerves were significantly higher than control values at 16-25 days. Oligodendrocytes, astrocytes, microgliacytes and unclassified cells were labelled in both normal and md rats. The mutants showed higher percentages of labelled astroglia and microglia, and the labelled oligodendroglia appeared immature when compared to the normal animals. Md optic nerves showed significantly higher counts of necrotic cells than controls at 14-30 days. Electron microscopy revealed the presence of abnormal oligodendrocytes, characterized by distended rough endoplasmic reticulum and a dilated perinuclear envelope, from 6 days of age in the mutant. These cells appear to degenerate and die. These results suggest a defect in the md rat oligodendrocyte, resulting in a protracted uptake of thymidine and increased cell death. Investigation of the link between these observations and the proposed myelin proteolipid protein defect in the md rat may reveal more about the role of myelin proteins in the CNS, and the specific cellular defect(s) in this mutant.

Transplantation of oligodendrocytes and Schwann cells into the spinal cord of the myelin-deficient rat.

Transplantation of oligodendrocytes or Schwann cells into the spinal cord of the newborn myelin-deficient (md) rat, an X-linked myelin mutant, was carried out and the extent of myelination of CNS axons studied. Dissociated glial cell suspensions, prepared from the spinal cords of female litter-mates, were injected into the lumbar spinal cord of 15 md rats and 5 normal litter-mates. In eight of the md rats examined 12 to 21 days post-transplantation patches of myelin produced by the transplanted oligodendrocytes were found in the dorsal or ventral columns. In two rats, small patches of myelination were found in more than one site. The myelin in these patches was positive on immunocytochemical staining for proteolipid protein. These observations were interpreted as evidence of the origin of this myelin from donor oligodendrocytes, as the md rat has an abnormality in synthesis of this protein. In addition, this myelin differed in its ultrastructure from host myelin, having a normal intraperiod line. Injection of cultured Schwann cells also resulted in extensive myelination of axons in the dorsal columns by these cells.

Myelin mosaicism in female heterozygotes of the canine shaking pup and myelin-deficient rat mutants.

Female heterozygotes of the shaking pup and myelin-deficient rat sex-linked recessive traits, show myelin mosaicism of the optic nerve and spinal cord. This is most marked in the optic nerve especially in the rat where mosaic patches persist with aging. In both the rat and dog, abnormal oligodendrocytes with distended rough endoplasmic reticulum are found in the abnormal patches and are a marker of the trait. Female heterozygote dogs can develop a marked tremor which disappears with age.