**4.4 Transgenic, mutant, and parabiotic mice**

The accessibility of mutant, transgenic, and probiotic experimental animal models could increase our knowledge about the mechanisms of myelin and axonal damage [81]. These models include mutant mice in which defects in myelin assembly occur. Another one is transgenic mice with deleted or inserted genes coding for immune components, and the other one is conditional knockout mice with genes manipulations in mature animals [82]. The generation of parabiotic mice has come about recently. The role of specific myelin proteins in myelin synthesis and remyelination has been examined in mutant mice in which the CNS myelin is affected. These include the Shiverer mouse in which the MBP gene is duplicated and inverted. Also, these consist of the Rumpshaker mouse with mutated proteolipid protein (PLP) Plp1 and the Jimpy mouse with the PLP gene mutation. These genetic mutations result in dysmyelination due to, for example, oligodendrocyte apoptosis and lastly neurodegeneration because of myelin damage. The importance of the role of immune responses in multiple sclerosis has led to the development of transgenic mice by focusing on myelin proteins or specific immune molecules. MOG-knockout mice have no recognizable phenotype. However, the use of its for EAE studies has revealed a major role for autoimmunity to MOG in chronic EAE in both mice and marmosets [70].

The parabiotic model is the act of living side-by-side [83]. Parabiotic studies involve suturing two mice together so blood vessels can connect, creating mice that share a common blood supply. Thus, the effect of the treatment of one mouse can be considered in the other mouse. Previous studies by using irradiation and separation of parabiotic mice indicated the importance of infiltrating monocytes in the induction of clinical signs of EAE [84]. Such surveys have been performed using transplantation of donor cells, although it has often been impossible to distinguish between donor cells and activated microglia from the host. Another study using

isochronic (same age) or heterochronic (same age) parabiotic mice indicates that exposure of young mice to the blood flow of old mice interferes with neurogenesis. This parabiotic study revealed age-related chemokines, suggesting the presence of rejuvenation factors. Heterochronic parabiotic mice are useful for understanding this point that remyelination is not merely more efficient in juvenile mice, but also some factors from juvenile mice can even restore the potential of remyelination in old mice [85].
