Cerebellar extinction lesions can manifest themselves with cerebellar motor and cerebellar cognitive affective syndromes. For investigation of the functions of the cerebellum and the pathogenesis of cerebellar diseases, particularly hereditary neurodegenerative cerebellar ataxias, various cerebellar mutant mice are used. The Lurcher mouse is a model of selective olivocerebellar degeneration with early onset and rapid progress. These mice show both motor deficits as well as cognitive and behavioral changes i.e., pathological phenotype in the functional domains affected in cerebellar patients. Therefore, Lurcher mice might be considered as a tool to investigate the mechanisms of functional impairments caused by cerebellar degenerative diseases. There are, however, limitations due to the particular features of the neurodegenerative process and a lack of possibilities to examine some processes in mice. The main advantage of Lurcher mice would be the expected absence of significant neuropathologies outside the olivocerebellar system that modify the complex behavioral phenotype in less selective models. However, detailed examinations and further thorough validation of the model are needed to verify this assumption.

• Klíčová slova
• Ataxia, Cerebellar Cognitive Affective Syndrome, Cerebellum, Lurcher Mouse, Validity,
• MeSH
• lidé MeSH
• modely nemocí na zvířatech * MeSH
• mozeček patologie   patofyziologie   MeSH
• myši - mutanty neurologické MeSH
• myši MeSH
• nemoci mozečku * genetika   patologie   patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Substitution of lost neurons by neurotransplantation would be a possible management of advanced degenerative cerebellar ataxias in which insufficient cerebellar reserve remains. In this study, we examined the volume and structure of solid embryonic cerebellar grafts in adult Lurcher mice, a model of olivocerebellar degeneration, and their healthy littermates. Grafts taken from enhanced green fluorescent protein (EGFP)-positive embryos were injected into the cerebellum of host mice. Two or six months later, the brains were examined histologically. The grafts were identified according to the EGFP fluorescence in frozen sections and their volumes were estimated using the Cavalieri principle. For gross histological evaluation, graft-containing slices were processed using Nissl and hematoxylin-eosin staining. Adjustment of the volume estimation approach suggested that it is reasonable to use all sections without sampling, but that calculation of values for up to 20% of lost section using linear interpolation does not constitute substantial error. Mean graft volume was smaller in Lurchers than in healthy mice when examined 6 months after the transplantation. We observed almost no signs of graft destruction. In some cases, compact grafts disorganized the structure of the host's cerebellar cortex. In Lurchers, the grafts had a limited contact with the host's cerebellum. Also, graft size was of greater variability in Lurchers than in healthy mice. The results are in compliance with our previous findings that Lurcher phenotype-associated factors have a negative effect on graft development. These factors can hypothetically include cerebellar morphology, local tissue milieu, or systemic factors such as immune system abnormalities.

• Klíčová slova
• Cerebellum, Lurcher mice, Neurotransplantation, Olivocerebellar degeneration,
• MeSH
• cerebelární ataxie patologie   MeSH
• modely nemocí na zvířatech * MeSH
• mozeček * patologie   MeSH
• myši transgenní * MeSH
• myši MeSH
• transplantace mozkové tkáně metody   MeSH
• zelené fluorescenční proteiny genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• enhanced green fluorescent protein MeSH Prohlížeč
• zelené fluorescenční proteiny MeSH

Cerebellar diseases causing substantial cell loss often lead to severe functional deficits and restoration of cerebellar function is difficult. Neurotransplantation therapy could become a hopeful method, but there are still many limitations and unknown aspects. Studies in a variety of cerebellar mutant mice reflecting heterogeneity of human cerebellar degenerations show promising results as well as new problems and questions to be answered. The aim of this work was to compare the development of embryonic cerebellar grafts in adult B6CBA Lurcher and B6.BR pcd mutant mice and strain-matched healthy wild type mice. Performance in the rotarod test, graft survival, structure, and volume was examined 2 months after the transplantation or sham-operation. The grafts survived in most of the mice of all types. In both B6CBA and B6.BR wild type mice and in pcd mice, colonization of the host's cerebellum was a common finding, while in Lurcher mice, the grafts showed a low tendency to infiltrate the host's cerebellar tissue. There were no significant differences in graft volume between mutant and wild type mice. Nevertheless, B6CBA mice had smaller grafts than their B6.BR counterparts. The transplantation did not improve the performance in the rotarod test. The study showed marked differences in graft integration into the host's cerebellum in two types of cerebellar mutants, suggesting disease-specific factors influencing graft fate.

• Klíčová slova
• Ataxia, Cerebellar degeneration, Lurcher mouse, Neurotransplantation, Pcd mouse,
• MeSH
• modely nemocí na zvířatech * MeSH
• mozeček fyziologie   transplantace   MeSH
• myši - mutanty neurologické MeSH
• myši inbrední C57BL MeSH
• myši inbrední CBA MeSH
• myši MeSH
• nemoci mozečku patologie   terapie   MeSH
• neurodegenerativní nemoci patologie   terapie   MeSH
• přežívání štěpu fyziologie   MeSH
• transplantace fetální tkáně metody   MeSH
• transplantace mozkové tkáně metody   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Restoration of damaged central nervous system structures, functional recovery, and prevention of neuronal loss during neurodegenerative diseases are major objectives in cerebellar research. The highly organized anatomical structure of the cerebellum with numerous inputs/outputs, the complexity of cerebellar functions, and the large spectrum of cerebellar ataxias render therapies of cerebellar disorders highly challenging. There are currently several therapeutic approaches including motor rehabilitation, neuroprotective drugs, non-invasive cerebellar stimulation, molecularly based therapy targeting pathogenesis of the disease, and neurotransplantation. We discuss the goals and possible beneficial mechanisms of transplantation therapy for cerebellar damage and its limitations and factors determining outcome.

• Klíčová slova
• Ataxias, Cerebellar reserve, Cerebellum, Neurotransplantation, Stem cells,
• MeSH
• buněčná a tkáňová terapie metody   MeSH
• nemoci mozečku terapie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

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.

• Klíčová slova
• Cerebellar degeneration, Cerebellum, Lurcher mouse, Purkinje cell, Transplantation,
• MeSH
• druhová specificita MeSH
• longitudinální studie MeSH
• metoda rotující tyčky MeSH
• modely nemocí na zvířatech MeSH
• motorické dovednosti MeSH
• mozeček embryologie   patologie   transplantace   MeSH
• myši - mutanty neurologické MeSH
• myši inbrední C3H MeSH
• myši inbrední CBA MeSH
• myši transgenní MeSH
• nemoci mozečku patologie   patofyziologie   terapie   MeSH
• neurodegenerativní nemoci patologie   patofyziologie   terapie   MeSH
• přežívání štěpu * fyziologie   MeSH
• transplantace mozkové tkáně * MeSH
• zelené fluorescenční proteiny genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• enhanced green fluorescent protein MeSH Prohlížeč
• zelené fluorescenční proteiny MeSH

Degenerative affections of nerve tissues are often accompanied by changes of vascularization. In this regard, not much is known about hereditary cerebellar degeneration. In this study, we compared the vascularity of the individual cerebellar components and the mesencephalon of 3-month-old wild type mice (n = 5) and Lurcher mutant mice, which represent a model of hereditary olivocerebellar degeneration (n = 5). Paraformaldehyde-fixed brains were processed into 18-μm thick serial sections with random orientation. Microvessels were visualized using polyclonal rabbit anti-laminin antibodies. Then, the stacks comprised of three 5-μm thick optical sections were recorded using systematic uniform random sampling. Stereological assessment was conducted based on photo-documentation. We found that each of the cerebellar components has its own features of vascularity. The greatest number and length of vessels were found in the granular layer; the number of vessels was lower in the molecular layer, and the lowest number of vessels was observed in the cerebellar nuclei corresponding with their low volume. Nevertheless, the nuclei had the greatest density of blood vessels. The reduction of cerebellum volume in the Lurcher mice was accompanied by a reduction in vascularization in the individual cerebellar components, mainly in the cortex. Moreover, despite the lower density of microvessels in the Lurcher mice compared with the wild type mice, the relative density of microvessels in the cerebellar cortex and nuclei was greater in Lurcher mice. The complete primary morphometric data, in the form of continuous variables, is included as a supplement. Mapping of the cerebellar and midbrain microvessels has explanatory potential for studies using mouse models of neurodegeneration.

• Klíčová slova
• Lurcher, blood microvessels, cerebellum, cerebral degeneration, laminin, mice, quantitative histology, stereology,
• Publikační typ
• časopisecké články MeSH

Hereditary cerebellar degenerations are a heterogeneous group of diseases often having a detrimental impact on patients' quality of life. Unfortunately, no sufficiently effective causal therapy is available for human patients at present. There are several therapies that have been shown to affect the pathogenetic process and thereby to delay the progress of the disease in mouse models of cerebellar ataxias. The second experimental therapeutic approach for hereditary cerebellar ataxias is neurotransplantation. Grafted cells might provide an effect via delivery of a scarce neurotransmitter, substitution of lost cells if functionally integrated and rescue or trophic support of degenerating cells. The results of cerebellar transplantation research over the past 30 years are reviewed here and potential benefits and limitations of neurotransplantation therapy are discussed.

• Klíčová slova
• Cerebellum, Hereditary cerebellar degeneration, Neurotransplantation,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

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.

• Klíčová slova
• Ataxia, Cerebellar transplantation, Gait analysis, Lurcher, Olivocerebellar degeneration,
• MeSH
• časové faktory MeSH
• chůze (způsob) MeSH
• metoda rotující tyčky MeSH
• mozeček embryologie   metabolismus   transplantace   MeSH
• mozkový neurotrofický faktor metabolismus   MeSH
• multisystémová atrofie patofyziologie   terapie   MeSH
• myši - mutanty neurologické MeSH
• myši inbrední C57BL MeSH
• myši inbrední CBA MeSH
• myši transgenní MeSH
• pohybová aktivita MeSH
• spinocerebelární degenerace patofyziologie   terapie   MeSH
• transplantace fetální tkáně metody   MeSH
• transplantace mozkové tkáně metody   MeSH
• výsledek terapie MeSH
• zelené fluorescenční proteiny genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• enhanced green fluorescent protein MeSH Prohlížeč
• mozkový neurotrofický faktor MeSH
• zelené fluorescenční proteiny MeSH

BACKGROUND: Neurotransplantation has great potential for future treatments of various neurodegenerative disorders. Preclinically, the Lurcher mutant mouse represents an appropriate model of genetically-determined olivocerebellar degeneration. The aim of the present study was to assess survival of naïve and neurally differentiated P19 carcinoma stem cells following transplantation into the cerebellum of Lurcher mice and wild type littermates. MATERIAL/METHODS: Adult normal wild type (n=51) and Lurcher mutant mice (n=87) of the B6CBA strain were used. The mean age of the animals at the time of transplantation was 261.5 days. Suspension of naive and neurally differentiated P19 carcinoma stem cells was injected into the cerebellum of the mice. In the Lurcher mutants, 2 depths of graft injection were used. Three weeks after implantation the brains of experimental animals were examined histologically. RESULTS: Survival of neuroprogenitor grafts at a depth of 1.6 mm was significantly higher in wild type vs. Lurcher mutant mice. In wild type mice, the typical graft localization was in the middle of the cerebellum, whereas in Lurcher mice the graft was never found inside the degenerated cerebellum and was primarily localized in the mesencephalon. CONCLUSIONS: We conclude that the appearance and low survival rate of cerebellar P19 carcinoma stem cell grafts in the Lurcher mutant mice weigh against the therapeutic value of this cell line in preclinical studies of neurodegeneration.

• MeSH
• mozeček cytologie   MeSH
• mutantní kmeny myší MeSH
• myši MeSH
• nádorové kmenové buňky cytologie   MeSH
• nervové kmenové buňky cytologie   MeSH
• přežívání štěpu MeSH
• transplantace kmenových buněk * MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH