Hereditary cerebellar ataxias are severe diseases for which therapy is currently not sufficiently effective. One of the possible therapeutic approaches could be neurotransplantation. Lurcher mutant mice are a natural model of olivocerebellar degeneration representing a tool to investigate its pathogenesis as well as experimental therapies for hereditary cerebellar ataxias. The effect of intracerebellar transplantation of embryonic cerebellar solid tissue or cell suspension on motor performance in adult Lurcher mutant and healthy wild-type mice was studied. Brain-derived neurotrophic factor level was measured in the graft and adult cerebellar tissue. Gait analysis and rotarod, horizontal wire, and wooden beam tests were carried out 2 or 6 months after the transplantation. Higher level of the brain-derived neurotrophic factor was found in the Lurcher cerebellum than in the embryonic and adult wild-type tissue. A mild improvement of gait parameters was found in graft-treated Lurcher mice. The effect was more marked in cell suspension grafts than in solid transplants and after the longer period than after the short one. Lurcher mice treated with cell suspension and examined 6 months later had a longer hind paw stride (4.11 vs. 3.73 mm, P < 0.05) and higher swing speed for both forepaws (52.46 vs. 32.79 cm/s, P < 0.01) and hind paws (63.46 vs. 43.67 cm/s, P < 0.001) than controls. On the other hand, classical motor tests were not capable of detecting clearly the change in the motor performance. No strong long-lasting negative effect of the transplantation was seen in wild-type mice, suggesting that the treatment has no harmful impact on the healthy cerebellum.
Lurcher mutant mice represent a natural model of genetically-determined olivocerebellar degeneration caused by a mutation in the δ2 glutamate receptor gene. They suffer from progressive postnatal loss of cerebellar Purkinje cells and a decrease of granule cells and inferior olive neurons. Their wild type littermates serve as healthy controls. A confocal laser scanning microscope was used aiming investigation the dynamics of changes in the cerebellar cortex of Lurcher and wild type mice derived from two strains during the period of 8-21 postnatal days. Fluorescent double-staining was used to visualize mainly the Purkinje cells in cerebellar slices. In wild types, only normal Purkinje cells of round or regular drop-shaped were present, when staining intensity of other individual cell structures differed in dependence on the age of the animal. In Lurcher mutants, there were still some normal-shaped cells. Nevertheless, depending on the animal's age, a wide variety of stages of the cell degeneration were depicted. The main characteristics of Purkinje cell degeneration in the early stage are: disruption of the continuity of the Purkinje cell layer, dark spots in cell nuclei and an irregular coloring of the cytoplasm. Later, the cells and their nuclei were deformed, often with two main dendrites sprouting from the cell body. Finally, the cell and nucleus margins were unclear, dendrites were significantly thickened, showing signs of shrinkage and fragmentation. Cell nucleoli underwent changes in number and appearance. No differences between the Lurcher mice of both strains (C3H and B6CBA) under examination were found.
For many degenerative cerebellar diseases, currently, no effective treatment that would substantially restore cerebellar functions is available. Neurotransplantation could be a promising therapy for such cases. Nevertheless, there are still severe limitations for routine clinical use. The aim of the work was to assess volume and morphology and functional impact on motor skills of an embryonic cerebellar graft injected in the form of cell suspension in Lurcher mutant and wild-type mice of the B6CBA and C3H strains after a 6-month survival period. The grafts survived in the majority of the mice. In both B6CBA and C3H Lurcher mice, most of the grafts were strictly delimited with no tendency to invade the host cerebellum, while in wild-type mice, graft-derived Purkinje cells colonized the host's cerebellum. In C3H Lurcher mice, but not in B6CBA Lurchers, the grafts had smaller volume than in their wild-type counterparts. C3H wild-type mice had significantly larger grafts than B6CBA wild-type mice. No positive effect of the transplantation on performance in the rotarod test was observed. The findings suggest that the niche of the Lurcher mutant cerebellum has a negative impact on integration of grafted cells. This factor seems to be limiting for specific functional effects of the transplantation therapy in this mouse model of cerebellar degeneration.
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