All Phenotypes Aptx<tm1Pmc> MGI Mouse

decreased survivor rate ( J:316365 )

• mice show reduced survival, with 53% of mice still alive at 400 days of age compared to 97% survival in wild-type controls

decreased body weight ( J:316365 )

• mice weigh about 35% less than controls

• adolescent mice at P45 weigh on average 30% less in males and 25% in females than controls

slow postnatal weight gain ( J:316365 )

• mice grow approximately 55% slower and reach plateau weights that are about 35% less than controls

abnormal motor coordination/balance ( J:316365 )

• motor coordination defects emerge between 210 and 400 days after birth

impaired righting response ( J:316365 )

• differences in motor function are first detectable at P8, where mice take 3-4 times longer on average to right themselves

ataxia ( J:316365 )

• mice develop severe and progressive ataxia

impaired coordination ( J:316365 )

• mice take twice as long to descend the vertical pole at P400 compared to controls

abnormal gait ( J:316365 )

• mice show a slower cadence and average speed across the gait platform at P400

• mice at P400, but not P210, need additional stabilization during ambulation, as they spend twice as much time with 3 paws rather than the normal 2, in contact with the ground as they walk across the gait analysis platform

increased thymoma incidence ( J:316365 )

abnormal Purkinje cell morphology ( J:316365 )

• somatic size of the Purkinje neurons is reduced

abnormal Purkinje cell dendrite morphology ( J:316365 )

• the primary and secondary dendrites of Purkinje neurons are abnormally large in caliber

thin cerebellar molecular layer ( J:316365 )

• the molecular layer width is normal in younger mice but progressively decreases in width at severity of ataxia increases

• however, no difference in the width of the granule cell layer is seen

cerebellum atrophy ( J:316365 )

• cerebellar atrophy develops as ataxia severity increases; cerebellum size is normal before P210, but by P210 the size is reduced, with continuing degenerative process to P460

• cerebellar atrophy is associated with selective reduction in the width of the molecular layer where Purkinje neuron dendrites reside

• cerebellar atrophy is not due to Purkinje neuron cell death as Purkinje neuron density is not different

neurodegeneration ( J:316365 )

• cerebellar neurodegeneration begins after P120

abnormal nervous system electrophysiology ( J:316365 )

• mice exhibit deficits in the ability of Purkinje neurons to fire continuously in response to current, with perturbations in the amplitude, threshold, and area of evoked action potentials

impaired neuron physiology ( J:316365 )

• Purkinje neurons show reduced spontaneous firing frequency; although slower Purkinje neuron firing rate is seen across most regions of the cerebellum, some subregions appear less impacted, including some areas of the lateral cerebellum, including the paraflocculus, paramedian, and crus I and II

• the most significant firing frequency decline occurs between P120 and 210

• Purkinje neurons exhibit tighter membranes, displaying higher membrane input resistances and a faster membrane time constant, indicating a reduced total membrane capacitance

abnormal synaptic physiology ( J:316365 )

• climbing fiber-to-Purkinje neuron synaptic responses depress at significantly greater magnitudes, with smaller overall width and decay time constant of the evoked currents

• however, synaptic properties of parallel fibers are normal, with no differences in short-term facilitation or halfwidth and decay time constant

increased excitatory postsynaptic current frequency ( J:316365 )

• spontaneous excitatory postsynaptic current (sEPSC) frequency is increased in granule cell-to-Purkinje neuron synapses

• however, mice show no difference in spontaneous excitatory postsynaptic current (sEPSC) size generated by granule cell-to-Purkinje neuron synapses, indicating the function of granule cell axon terminals (parallel fiber inputs) is normal in the cerebellum

abnormal T cell differentiation ( J:316365 )

• mice exhibit elevated proportions of CD44+CD25- (DN1 stage), CD44+CD25+ (DN2 stage), and CD44-CD25+ (DN3 stage) cells and lower CD44-CD25- (DN4 stage), indicating an impediment of CD44-CD25+ cells maturing into CD44-CD25- double negative cells

increased CD8-positive, alpha-beta T cell number ( J:316365 )

• the proportion of CD8+ T-cells is increased

decreased T cell number ( J:316365 )

• reduction in the total fraction of CD3+ T-cells in the peripheral blood

abnormal CD4-positive helper T cell morphology ( J:316365 )

• reduction in the percentage of T-cells is peripheral blood is mostly associated with a reduction in the CD4+ helper T-cell population