Jan Cendelin

Purkinje cell loss affects differentially the execution, acquisition and prepulse inhibition of skeletal and facial motor responses in Lurcher mice

Adult heterozygous Lurcher mice show a degeneration of almost all Purkinje cells and 90% of the granular cells of the cerebellum, resulting in ataxia or general deficits in motor coordination. These mice are therefore an excellent model for studying the role of the cerebellar cortex in motor performance, including the acquisition of new motor abilities. The performance of 3‐month‐old Lurcher mice was studied in various behavioural (fall, horizontal bar, rotating cylinder, and ladder), spatial orientation (water maze) and associative learning (eyelid classical conditioning) tasks and compared with that of wild‐type mice. Behavioural tasks indicated a deficit for motor abilities in Lurcher mice but with some adaptation to the tests and improvement in performance. Wild‐type and Lurcher mice performed swimming equally, but the latter learned the task significantly more slowly than the former. The late component of reflex blinks was smaller in amplitude and had a longer latency in Lurcher mice than in controls. Learning curves for Lurcher mice during classical conditioning of eyelid responses were similar to controls, but the amplitude of the learned response in Lurcher mice was significantly lower. The startle response to a severe tone was similar in both control and Lurcher mice but the latter were unable to produce prepulse inhibition. These results suggest that the cerebellar cortex is not indispensable for the performance of this complete set of skeletal and facial tasks, or for the acquisition of new motor abilities, but it is for the appropriate execution and adjustment of any of these motor activities.

Ataxic gait analysis in a mouse model of the olivocerebellar degeneration

Lurcher mutant mice represent a model of olivocerebellar degeneration. Postnatally, a complete loss of Purkinje cells and secondary reduction of granule cells and inferior olive neurons occurs. Cerebellar ataxia is among the symptoms of degeneration of the cerebellum. The aim of the work was to identify gait parameters which are changed in Lurcher mice due to cerebellar ataxia arising from functional cerebellar decortication, and to assess the correlation between gait parameters, walking speed and performance in rotarod test. We used the adult Lurcher mutant and wild type mice of the B6CBA strain. For gait analysis the CatWalk system was used. Motor functions were examined with the rotarod. Data analysis revealed significant differences between Lurchers and controls in many gait parameters. However, almost all parameters correlated with the walking speed and the differences disappeared after the correction to the walking speed. The question is what is the primary change in Lurchers-whether the walking speed or individual gait parameters. In the rotarod test, the Lurcher mutants revealed significantly worse results than the wild type animals. No correlation between the gait parameters and performance in the rotarod test was found.

The effect of repeated rotarod training on motor skills and spatial learning ability in Lurcher mutant mice

Lurcher mutant mice represent a model of olivocerebellar degeneration. Due to loss of Purkinje cells, they suffer from functional cerebellar decortication resulting in ataxia and deterioration of cognitive functions. The aim of the work was to assess the effect of enforced physical activity represented by rotarod training on motor skills and spatial learning in young and adult B6CBA Lurcher mice. These functions were compared with those in untrained wild type mice of the same age. We examined motor skills using bar, ladder and rotarod tests. Spatial learning was tested in the Morris water maze. Motor skills of Lurchers were found to be worse than in wild type mice, but they showed motor learning in the course of training. The training did not significantly influence the results on the bar and ladder. In the rotarod test, young trained Lurchers achieved only slightly better results than untrained ones. In adult mice, the improvement was insignificant. Lurchers failed in spatial learning test compared to the wild type mice. In the wild type mice there was no difference in learning between young and adult individuals, while young Lurchers learned better than older ones. Enforced motor activity led to spatial learning improvement in older Lurchers, but not in young ones. The experiments showed that effects of enforced physical activity in Lurcher mice mitigated the deficit in the water maze task related to age so that trained older Lurchers showed as good performance as younger ones but still worse than the wild type mice.

Behavioral Characteristics, Associative Learning Capabilities, and Dynamic Association Mapping in an Animal Model of Cerebellar Degeneration

Young adult heterozygous Lurcher mice constitute an excellent model for studying the role of the cerebellar cortex in motor performance-including the acquisition of new motor abilities-because of the early postnatal degeneration of almost all of their Purkinje and granular cells. Wild-type and Lurcher mice were classically conditioned for eyelid responses using a delay paradigm with or without an electrolytic lesion in the interpositus nucleus. Although the late component of electrically evoked blink reflexes was smaller in amplitude and had a longer latency in Lurcher mice than that in controls, the two groups of animals presented similar acquisition curves for eyeblink conditioning. The lesion of the interpositus nucleus affected both groups of animals equally for the generation of reflex and conditioned eyelid responses. Furthermore, we recorded the multiunitary activity at the red and interpositus nuclei during the same type of associative learning. In both nuclei, the neural firing activity lagged the beginning of the conditioned response (determined by orbicularis oculi muscle response). Although red nucleus neurons and muscle activities presented a clear functional coupling (strong correlation and low asymmetry) across conditioning, the coupling between interpositus neurons and either red nucleus neurons or muscle activities was slightly significant (weak correlation and high asymmetry). Lurcher mice presented a nonlinear coupling (high asymmetry) between red nucleus neurons and muscle activities, with an evident compensatory adjustment in the correlation of firing between interpositus and red nuclei neurons (a coupling with low asymmetry), aimed probably at compensating the absence of cerebellar cortical neurons.

From mice to men: lessons from mutant ataxic mice.

Ataxic mutant mice can be used to represent models of cerebellar degenerative disorders. They serve for investigation of cerebellar function, pathogenesis of degenerative processes as well as of therapeutic approaches. Lurcher, Hot-foot, Purkinje cell degeneration, Nervous, Staggerer, Weaver, Reeler, and Scrambler mouse models and mouse models of SCA1, SCA2, SCA3, SCA6, SCA7, SCA23, DRPLA, Niemann-Pick disease and Friedreich ataxia are reviewed with special regard to cerebellar pathology, pathogenesis, functional changes and possible therapeutic influences, if any. Finally, benefits and limitations of mouse models are discussed.

Near‐complete adaptation of the PRiMA knockout to the lack of central acetylcholinesterase

J. Neurochem. (2012) 122, 1065–1080.

The Effect of Cerebellar Transplantation and Enforced Physical Activity on Motor Skills and Spatial Learning in Adult Lurcher Mutant Mice

Lurcher mutant mice represent a model of olivocerebellar degeneration. They are used to investigate cerebellar functions, consequences of cerebellar degeneration and methods of therapy influencing them. The aim of the work was to assess the effect of foetal cerebellar graft transplantation, repeated enforced physical activity and the combination of both these types of treatment on motor skills, spontaneous motor activity and spatial learning ability in adult B6CBA Lurcher mice. Foetal cerebellar grafts were applied into the cerebellum of Lurchers in the form of solid tissue pieces. Enforced motor activity was realised through rotarod training. Motor functions were examined using bar, ladder and rotarod tests. Spatial learning was tested in the Morris water maze. Spontaneous motor activity in the open field was observed. The presence of the graft was examined histologically. Enforced physical activity led to moderate improvement of some motor skills and to a significant amelioration of spatial learning ability in Lurchers. The transplantation of cerebellar tissue did not influence motor functions significantly but led to an improvement of spatial learning ability. Mutual advancement of the effects of both types of treatment was not observed. Spontaneous motor activity was influenced neither by physical activity nor by the transplantation. Physical activity did not influence the graft survival and development. Because nerve sprouting and cell migration from the graft to the host cerebellum was poor, the functional effects of the graft should be explained with regard to its trophic influence rather than with any involvement of the grafted cells into neural circuitries.

Effect of dimethyl sulfoxide in cerebellar mutant Lurcher mice.

DMSO has been many times described as harmless substance, beneficial in various diseases or pathological states, including brain injury or ischemia. Using Lurcher mutant mice suffering from genetically determined olivocerebellar degeneration and normal wild type mice, we examined the effect of DMSO on spontaneous motor activity and spatial learning and orientation ability. The acute effect of DMSO was studied in mice aged 3, 6, 9 and 22 weeks. DMSO treatment decreased spontaneous activity in the open field and swimming speed in the Morris water maze in both Lurcher mutant and wild type mice. While saline-treated Lurcher mice showed age-related decline of spatial memory in the Morris water maze in DMSO-treated ones such decline did not occur. The mechanism of the effect of DMSO remains unclear. A possible explanation could be modulation of the brain perfusion and metabolism in the aging brain. The improvement of learning ability could be also mediated by a tranquilizing effect of DMSO reducing stress-induced behavioral disinhibition which is supposed to interfere with learning process in Lurcher mutants. Future studies which would investigate DMSO effects in other models of neurodegenerative diseases are necessary to verify its potential therapeutic impact.

Intracerebellar application of P19-derived neuroprogenitor and naive stem cells to Lurcher mutant and wild type B6CBA mice

Summary 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.

A Preliminary Study of Solid Embryonic Cerebellar Graft Survival in Adult B6CBA Lurcher Mutant and Wild Type Mice

Lurcher mutant mice represent a model of olivocerebellar degeneration. They suffer from complete loss of Purkinje cells and a reduction of granule cells and inferior olive neurons. Their wild type littermates serve as healthy controls. The aim of the work was to compare solid embryonic cerebellar graft survival within a period of 9 weeks after their transplantation in adult Lurcher mutant and wild type mice of the B6CBA strain. The solid grafts were injected through a hole in the occipital bone. Host mice were sacrificed 3, 6, or 9 weeks after the transplantation and their cerebella and brain‐stems were examined histologically to assess graft presence and structure. We did not find significant differences in graft survival rates between Lurcher mutant and wild type mice. The frequency of graft presence did not differ between mice examined 3, 6, and 9 weeks after the transplantation, neither in Lurchers nor in wild type mice. The grafts were of various sizes. In some cases, only small residua of the grafts were found. Nerve fiber sprouting and cell migration from the graft to the host tissue were observed more often in wild type mice than in Lurchers when examined 6 weeks after surgery. In the period 3–9 weeks after transplantation, massive dying out of the grafts was not observed despite regressive processes in some of the grafts. The degenerative changes in the Lurcher mutant cerebellum do not have strong impact on the fate of the solid cerebellar graft. Anat Rec, 292:1986–1992, 2009.