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Exercise therapy represents an important tool for the treatment of many neurological diseases, including cerebellar degenerations. In mouse models, exercise may decelerate the progression of gradual cerebellar degeneration via potent activation of neuroprotective pathways. However, whether exercise could also improve the condition in mice with already heavily damaged cerebella remains an open question. Here we aimed to explore this possibility, employing a mouse model with dramatic early-onset cerebellar degeneration, the Lurcher mice. The potential of forced physical activity and environmental enrichment (with the possibility of voluntary running) for improvement of behaviour and neuroplasticity was evaluated by a series of behavioural tests, measuring BDNF levels and using stereological histology techniques. Using advanced statistical analysis, we showed that while forced physical activity improved motor learning by ∼26 % in Lurcher mice and boosted BDNF levels in the diseased cerebellum by 57 %, an enriched environment partially alleviated some behavioural deficits related to behavioural disinhibition. Specifically, Lurcher mice exposed to the enriched environment evinced reduced open arm exploration in elevated plus maze test by 18 % and increased immobility almost 9-fold in the forced swim test. However, we must conclude that the overall beneficial effects were very mild and much less clear, compared to previously demonstrated effects in slowly-progressing cerebellar degenerations., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Hereditary cerebellar degenerations are severe and complex diseases for which there is currently no effective causal treatment. A hopeful method could be the support of plasticity or neurotransplantation. However, there are still many unknown aspects which could influence the outcome of treatment. As neurotrophic factors are essential in neuroplasticity and neuronal integration, potential abnormalities in their levels could be involved in the pathogenesis of the disease and would possibly explain the unsuitability of diseased cerebellum for the graft integration. The aim of this study was to identify and compare basal levels of trophic factors BDNF and GDNF in the cerebellum in two mouse models of cerebellar degeneration - Lurcher and pcd. Basal levels of BDNF in the cerebellum have been shown to be lower in both mutant models than in healthy controls. However, the GDNF levels were surprisingly increased in the cerebella of Lurcher mutant mice compared to both wild type and pcd mice. In addition, a different distribution of GFAP-positive cells in the cerebellum was revealed in Lurcher mice. These differences suggest that the niche of the Lurcher mutant cerebellum is changed. The question, however, remains how these changes are related to the neurodegenerative process and how they could influence potential compensatory mechanisms, plasticity and response to therapeutic interventions., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Spinocerebellar ataxia 1 (SCA1) is a devastating neurodegenerative disease associated with cerebellar degeneration and motor deficits. However, many patients also exhibit neuropsychiatric impairments such as depression and apathy; nevertheless, the existence of a causal link between the psychiatric symptoms and SCA1 neuropathology remains controversial. This study aimed to explore behavioral deficits in a knock-in mouse SCA1 (SCA1 154Q/2Q ) model and to identify the underlying neuropathology. We found that the SCA1 mice exhibit previously undescribed behavioral impairments such as increased anxiety- and depressive-like behavior and reduced prepulse inhibition and cognitive flexibility. Surprisingly, non-motor deficits characterize the early SCA1 stage in mice better than does ataxia. Moreover, the SCA1 mice exhibit significant hippocampal atrophy with decreased plasticity-related markers and markedly impaired neurogenesis. Interestingly, the hippocampal atrophy commences earlier than the cerebellar degeneration and directly reflects the individual severity of some of the behavioral deficits. Finally, mitochondrial respirometry suggests profound mitochondrial dysfunction in the hippocampus, but not in the cerebellum of the young SCA1 mice. These findings imply the essential role of hippocampal impairments, associated with profound mitochondrial dysfunction, in SCA1 behavioral deficits. Moreover, they underline the view of SCA1 as a complex neurodegenerative disease and suggest new avenues in the search for novel SCA1 therapies.

Lurcher mutant mice of the C3H strain provide a model of both cerebellar and retinal degeneration. Therefore, they enable the study of the behavior of cerebellar mutants under disabled visual orientation conditions. We aimed to examine cerebellar Lurcher mutants and wild type mice with intact cerebella with and without retinal degeneration employing the rotarod and Morris water maze tests. The positions of the hidden platform and the starting point in the water maze test were stable so as to enable the use of both idiothetic navigation and visual inputs. The Lurcher mice evinced approximately 90 % shorter fall latencies on the rotarod than did the wild type mice. Retinal degeneration exerted no impact on motor performance. Only the wild type mice with normal retina were able to find the water maze platform efficiently. The wild type mice with retinal degeneration developed immobility (almost 25 % of the time) as a sign of behavioral despair. The Lurchers maintained high swimming activity as a potential manifestation of stress-induced behavioral disinhibition and their spatial performance was related to motor skills and swim speed. We demonstrated that both motor deficit and pathological behavior have the potential to contribute to abnormal performance in spatial tasks. Thus, spatial disability in cerebellar mutants is most likely a complex consequence of multiple disturbances related to cerebellar dysfunction., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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.

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.

Edaravone is a mitochondrially targeted drug with a suggested capability to modify the course of diverse neurological diseases. Nevertheless, edaravone has not been tested yet in the context of spinocerebellar ataxia 1 (SCA1), an incurable neurodegenerative disease characterized mainly by cerebellar disorder, with a strong contribution of inflammation and mitochondrial dysfunction. This study aimed to address this gap, exploring the potential of edaravone to slow down SCA1 progression in a mouse knock-in SCA1 model. SCA1154Q/2Q and healthy SCA12Q/2Q mice were administered either edaravone or saline daily for more than 13 weeks. The functional impairments were assessed via a wide spectrum of behavioral assays reflecting motor and cognitive deficits and behavioral abnormalities. Moreover, we used high-resolution respirometry to explore mitochondrial function, and immunohistochemical and biochemical tools to assess the magnitude of neurodegeneration, inflammation, and neuroplasticity. Data were analyzed using (hierarchical) Bayesian regression models, combined with the methods of multivariate statistics. Our analysis pointed out various previously documented neurological and behavioral deficits of SCA1 mice. However, we did not detect any plausible therapeutic effect of edaravone on either behavioral dysfunctions or other disease hallmarks in SCA1 mice. Thus, our results did not provide support for the therapeutic potential of edaravone in SCA1. [ABSTRACT FROM AUTHOR]