growth/size/body
• ataxic mice are significantly smaller than control littermates
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• body weights of ataxic mice are significantly reduced at 4, 8, and 16 weeks of age
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behavior/neurological
• frequent limb-clasping after 12 weeks of age
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• mice begin to fall frequently after weaning (3 weeks of age), most likely due to abnormal control of their hind limbs
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• mice display a difficulty to right themselves
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• mice develop a slowly progressive ataxia starting at ~3 weeks of age
• ataxic mice exhibit typical traits of paraplegia but no signs of spasticity
• some mice develop mild appendicular ataxia, including the fore limbs
• rates of ataxic progression show individual variations
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• at 6 weeks of age, mice begin to walk dragging their hind limbs
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• mice move their toes parallel to the direction of movement and do not attach their heels on the ground
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• mice exhibit a short-stepped gait
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• hind limbs become entirely paralyzed in many cases
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nervous system
• EM revealed lipofuscin accumulation in Purkinje cell bodies, representing senescent postmitotic neurons at 30 weeks of age
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• mice show abnormal Purkinje cell dendrite branching and significantly thicker dendrites at 30 weeks of age
• dendritic spines are smaller and abnormally shaped; thin (filopodia-like or headed) spines are predominant indicating a deficit in spine maturation, while stubby or mushroom-shaped spines, typical of normal and mature PCs, are significantly decreased
• however, dendritic spine density is similar to that of wild-type controls
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• average Purkinje cell number is significantly decreased in cerebellar lobules VII and VIII at 30 weeks of age
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• mice show a significant reduction in granule cell density at 30 weeks of age
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• VGluT2-positive climbing fiber (CF) terminals are markedly increased in number and distributed throughout the full extent of the molecular layer, unlike in control mice where CF terminals are distributed along calbindin-stained Purkinje cell dendrites in the basal four-fifths of the molecular layer
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• some mice exhibit significant atrophy of the anterior folia where the anterior part of the cerebellar folia is significantly smaller in size than its posterior counterpart; in other mutants, however, neither the anterior part nor the whole cerebella are smaller than those of controls
• average Purkinje cell number is significantly decreased in cerebellar lobules VII and VIII at 30 weeks of age
• however, cerebellar foliation, laminated organization, and monolayer alignment of Purkinje cells are normal
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• relative cerebellar size (cerebellum/cerebrum) is significantly smaller than that of control littermates
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• all ataxic mice exhibit significant cerebellar atrophy, as shown by micro-MRI and histological analysis
• severity of cerebellar atrophy varies between individual mice
• however, the spinal cord and sciatic nerves appear morphologically normal at 4 months of age
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• affected mice show impaired parallel fiber- Purkinje cell (PF-PC) synapse formation in the cerebellum at 4 months of age
• ~17% of mutant synapses are mismatched i.e. the postsynaptic density of the PC spine is significantly longer than the active zone of the PF terminal
• ~40% of PC spines are "free" i.e. lacking synaptic contact with PF terminals
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reproductive system
• both male and female mutant mice fail to produce offspring under natural breeding conditions, likely due to ataxia
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