Analysis Tools
mortality/aging
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• most mutant mice die at weaning (P21)
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• mutant mice that survive weaning usually die shortly afterwards (up to P33)
• removal of wild-type and heterozygous mice from the cage significantly improves survival but does not ameliorate the neurological deficits
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behavior/neurological
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• tremors accentuated upon movement, first evident at P11 and reaching maximal severity at P21
• upon removal of wild-type and heterozygous mice from the cage, tremors improve slighly but worsen at ~5 months of age
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• at P21 or later, mutant mice are unable to maintain their balance on a stationary beam
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• unable to remain on a rotarod for more than a few seconds
• rotarod performance does not improve with practice
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• mice are unable to hold on to the beam in beam walking trials indicating a severe motor dysfunction
• mice start to fall off the rotarod when it starts to accelerate, indicating severe fine motor coordination defects
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• mutant mice are unable to support their weight against gravity, hold onto the edge of a cage, or climb a rope
• upon removal of wild-type and heterozygous mice from the cage, weakness improves slightly but worsens at ~5 months of age
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• wide-based gait suggestive of cerebellar dysfunction, first evident at P11 and reaching maximal severity at P21
(J:69621)
• ataxic gait
(J:107653)
• shuffling footprint pattern
(J:107653)
• widened stance
(J:107653)
• lack of fore-hind foot correspondence
(J:107653)
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• hypomotility first evident at P11, reaching maximal severity at P21
• at P21, P40 and P100, mutant mice are almost immobile in open field tests
• upon removal of wild-type and heterozygous mice from the cage, hypoactivity improves at later time points but worsens at ~5 months of age
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growth/size/body
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• reduced body size starting at P11
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• at P35, mutants weigh about half the weight of wild-type littermates (8g vs 17g, respectively)
• upon removal of wild-type and heterozygous mice from the cage, mutants slowly increase in size and males eventually approach normal weight
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nervous system
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• loss of axoglial junctions
(J:107653)
• paranodal transverse septa are absent
(J:107653)
• disorganized and misoriented microtubules
(J:107653)
• thinner myelin sheath
(J:162215)
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• large numbers of axonal swellings on Purkinje cells
(J:107653)
• accumulation of mitochondria in axonal swellings
(J:107653)
• accumulation of smooth endoplasmic reticulum and mitochondria in nodal and paranodal regions of Purkinje cell axons
(J:162215)
• extreme buildup of smooth endoplasmic reticulum and mitochondria in axonal swellings
(J:162215)
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• distribution of basket neuron axon terminals is altered by Purkinje cell axon swelling
• atrophy in the molecular layer of the cerebellum at 14 months
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• in the CNS, the paranodal and nodal morphology is frequently perturbed, resulting in aberrant organization and abnormal axon-glial interactions in the paranodal region
• a striking loss of the regular array of transverse bands between paranodal loops and the axon is observed; occasionally, irregular densities are noted between the glial loops and the axon
• "everted loops" (i.e. paranodal loops facing away from, rather than towards, the axonal membrane) are frequently observed in mutant, but not wild-type, spinal cords
• in other CNS sites, the loops are severely disorganized in the paranodal region
• a global deficiency of paranodal components (contactin and neurofascin) is observed, contributing to the defects in glial loop adhesion
• moreover, the strict delineation between Na+ channels at the node and K+ channels at the juxtaparanode is abolished in mutant sciatic and optic nerves, with K+ channels displaced into the paranodal domains and slighly overlapping with Na+ channels
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• in the CNS, the morphological organization of the paranodal region is often grossly disrupted, as shown by the striking eversion of glial loops
(J:69621)
• often, only the paranodal loops of the innermost myelin turns remain attached to the axon, whereas the lateral loops of the outermost turns are often unattached, everted or displaced medially, indicating that the normal trapezoid organization of the myelin sheath is reversed
(J:69621)
• other defects, including loops from a single myelin sheath that appose each other and myelin segments that overlap, suggest defective glial attachment
(J:69621)
• thinner myelin sheath on Purkinje cell axons
(J:162215)
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• hypomyelination in both the CNS and PNS
• g-ratio of white matter myelinated axons is increased in both the CNS and PNS at 2 months of age and in small axons, the g-ratio is increased even more
• axons with a higher g-ratio are more frequent compared to controls; 85.9% of mice show axons with a g-ratio of 0.75 or above compared to 0% in controls
• mice show an increase in the proportion of unmyelinated axons (5.5% compared to 0.9% in controls)
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• at P44-P45, mutants display a mild hypermyelination, as evidenced by a slight increase in the myelin thickness of some, but not all, sciatic nerves examined
• however, compact myelin formation remains largely unaffected
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• compound action potential (CAP) peak-to-peak amplitudes are significantly reduced in mutant mice (45% at both maximal and half-maximal stimulation)
• unlike wild-type CAPs which display a smooth waveform, CAPs of mutant sciatic nerves display a delayed deflection
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• nerve conduction amplitudes for the sciatic nerve and the ankle region are reduced at P30
• the latency measuring the time taken for the fastest nerve fibers to conduct between the two stimulation points is increased for the sciatic nerve
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• at P47 to P107, low-frequency stimulation of mutant sciatic nerves at maximal intensity indicates a 41% reduction in nerve conduction velocity relative to wild-type nerves; a 42% reduction is observed with low-frequency stimulation at half-maximal intensity
(J:69621)
• nerve conduction velocities for the sciatic nerve and the ankle region are reduced at P30
(J:342323)
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muscle
muscle spasm
(
J:69621
)
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• occasional extensor spasms of the lower extremities
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skeleton
