T(2)-weighted microMRI and evoked potential of the visual system measurements during the development of hypomyelinated transgenic mice.

Our objective was to follow the course of a dysmyelinating disease followed by partial recovery in transgenic mice using non-invasive high-resolution (117 x 117 x 70 microm) magnetic resonance (microMRI) and evoked potential of the visual system (VEP) techniques. We used JOE (for J37 golli overexpressing) transgenic mice engineered to overexpress golli J37, a product of the Golli-mbp gene complex, specifically in oligodendrocytes. Individual JOE transgenics and their unaffected siblings were followed from 21 until 75-days-old using non-invasive in vivo VEPs and 3D T2-weighted microMRI on an 11.7 T scanner, performing what we believe is the first longitudinal study of its kind. The microMRI data indicated clear, global hypomyelination during the period of peak myelination (21-42 days), which was partially corrected at later ages (>60 days) in the JOE mice compared to controls. These microMRI data correlated well with [Campagnoni AT (1995) "Molecular biology of myelination". In: Ransom B, Kettenmann H (eds) Neuroglia--a Treatise. Oxford University Press, London, pp 555-570] myelin staining, [Campagnoni AT, Macklin WB (1988) Cellular and molecular aspects of myelin protein gene-expression. Mol Neurobiol 2:41-89] a transient intention tremor during the peak period of myelination, which abated at later ages, and [Lees MB, Brostoff SW (1984) Proteins in myelin. In: Morell (ed) Myelin. Plenum Press, New York and London, pp 197-224] VEPs which all indicated a significant delay of CNS myelin development and persistent hypomyelination in JOE mice. Overall these non-invasive techniques are capable of spatially resolving the increase in myelination in the normally developing and developmentally delayed mouse brain.

Myelin deficiencies visualized in vivo: visually evoked potentials and T2-weighted magnetic resonance images of shiverer mutant and wild-type mice.

Visually evoked potentials (VEPs) and micro magnetic resonance imaging (micro MRI) are widely used as noninvasive techniques for diagnosis of central nervous system (CNS) diseases, especially myelin diseases, such as multiple sclerosis. Here we use these techniques in tandem to validate the in vivo data in mouse models. We used the shiverer mutant mouse, which has little or no CNS myelin, as a test model. These data show that shiverer (MBP(shi)/MBP(shi)) has a VEP latency that is 30% longer than that of its wild-type sibling. Surprisingly, the heterozygous (MBP(shi)/+) mouse, with apparently normal myelin, nevertheless has a 7% increase in its VEP latency vs. wild type. The micro MRIs of the same animals show that myelinated white matter is hypointense compared with gray matter as a result of the shorter T2 in myelinated regions of the CNS. T2-weighted images of wild-type and heterozygous shiverer mice show regions of hypointensity corresponding to the major myelinated tracts, including the optic nerve and the optic tract of the CNS, whereas shiverer mice have no regions of low intensity and therefore no detectable myelinated areas. In shiverer mice, micro MRI can discern hypomyelination throughout the brain, including the optic tract, and these changes correlate with longer VEP latencies. In addition, VEPs can also detect changes in the molecular make up of myelin that are not discernible with histology or micro MR. These data show the potential of using micro MRI in combination with VEPs to follow changes in both the quality and the quantity of myelin in vivo. These combined methods would be useful for longitudinal studies and therapy testing.

Region-specific myelin pathology in mice lacking the golli products of the myelin basic protein gene.

The myelin basic protein (MBP) gene encodes two families of proteins, the classic MBP constituents of myelin and the golli-MBPs, the function of which is less well understood. In this study, targeted ablation of the golli-MBPs, but not the classic MBPs, resulted in a distinct phenotype unlike that of knock-outs (KOs) of the classic MBPs or other myelin proteins. Although the golli KO animals did not display an overt dysmyelinating phenotype, they did exhibit delayed and/or hypomyelination in selected areas of the brain, such as the visual cortex and the optic nerve, as determined by Northern and Western blots and immunohistochemical analysis with myelin protein markers. Hypomyelination in some areas, such as the visual cortex, persisted into adulthood. Ultrastructural analysis of the KOs confirmed both the delay and hypomyelination and revealed abnormalities in myelin structure and in some oligodendrocytes. Abnormal visual-evoked potentials indicated that the hypomyelination in the visual cortex had functional consequences in the golli KO brain. Evidence that the abnormal myelination in these animals was a consequence of intrinsic problems with the oligodendrocyte was indicated by an impaired ability of oligodendrocytes to form myelin sheets in culture and by the presence of abnormal Ca2+ transients in purified cortical oligodendrocytes studied in vitro. The Ca2+ results reported in this study complement previous results implicating golli proteins in modulating intracellular signaling in T-cells. Together, all these findings suggest a role for golli proteins in oligodendrocyte differentiation, migration, and/or myelin elaboration in the brain.