behavior/neurological phenotype

• abnormal behavior
  • in the Barnes circular maze test, males are able to locate the correct target hole where the escape box had been in the probe trial, however they spend less time around the target hole than wild-type mice
  (MGI Ref ID J:174441)
  • in the Y-maze test, the total percentage of alternations is decreased indicating impaired spontaneous alternation
  (MGI Ref ID J:174441)

• abnormal contextual conditioning behavior
  • in the contextual fear conditioning test, mutants show decreased immobility in the fourth time point only
  (MGI Ref ID J:174441)

• abnormal emotion/affect behavior
  • in a portion of the Porsolt forced swim test, mutants show decreased immobility time and increased distance traveled, suggesting that despair-like behavior might be decreased, however, generally over the entire test, no statistical significance is seen for immobility
  (MGI Ref ID J:174441)
  • r immobility
  (MGI Ref ID J:174441)

• abnormal social investigation
  • Normal - however, no differences were seen in the social interaction test of a one-chamber novel environment
  (MGI Ref ID J:174441)
  • in Crawley's three-chamber social approach test, males spend a shorter time with stranger mice than with familiar mice compared to wild-type mice which spend more time with stranger mice, indicating some impaired sociability or object recognition memory
  (MGI Ref ID J:174441)

• decreased anxiety-related response
  • in the elevated plus-maze test, entries into and time spent on the open arms is increased and in the open field test, time spent in the center of the field is increased, indicating decreased anxiety-like behavior
  (MGI Ref ID J:174441)

• decreased thermal nociceptive threshold
  • males exhibit decreased thresholds in the hot plate test, indicating increased antinociceptive responses
  (MGI Ref ID J:174441)

• hyperactivity
  • in the open field test, 14 week old males show an increase in total locomotive distance and an increase in stereotypic locomotion
  (MGI Ref ID J:174441)
  • in the Y-maze test, males show increased numbers of entries into each arm, total alternations, and total distance traveled indicating hyperactivity
  (MGI Ref ID J:174441)

• increased vertical activity
  • vertical activity of 14 week old males is increased in the latter half of the open field test
  (MGI Ref ID J:174441)

integument phenotype

• decreased thermal nociceptive threshold
  • males exhibit decreased thresholds in the hot plate test, indicating increased antinociceptive responses
  (MGI Ref ID J:174441)

nervous system phenotype

• increased prepulse inhibition
  • males younger than 6 months of age exhibit lower startle amplitudes than wild-type mice at 110 dB and 120 dB and an increase in percent prepulse inhibition
  (MGI Ref ID J:174441)

• tau protein deposits
  • hyperphosphorylated tau protein accumulation is seen in the lateral globus pallidus, amygdala, auditory cortex, ventral hippocampus, the cingulate cortex, anterior cortical amygdaloid nucleus, and dorsal hippocampus at 4 months of age
  (MGI Ref ID J:174441)

behavior/neurological phenotype

• abnormal sexual interaction
  • homozygous females do not mate, so mice have to be maintained as hemizygotes
  (MGI Ref ID J:119741)

behavior/neurological phenotype

• abnormal spatial learning
  • 6 month old females are able to learn to locate the platform of the Morris water maze during training and latencies to find the visible platform are similar between mutants and wild-type mice, however mutants spend more time in finding the invisible platform, indicating impaired spatial learning ability
  (MGI Ref ID J:174441)
  • during the probe trail of the Morris water maze, mutant females show less time and path length in the pool quadrant where the platform had previously been placed and a smaller number of target platform crossings
  (MGI Ref ID J:174441)
  • orm, indicating impaired spatial learning ability
  (MGI Ref ID J:174441)

• hunched posture
  (MGI Ref ID J:165441)
  • paralysis is associated with hunched-back posture
  (MGI Ref ID J:119741)

• limb grasping
  • at 3 months of age, mice exhibit limb grasping and limb retraction when lifted by the tail, whereas mice expressing a wild-type MAPT transgene show no neurodegenerative phenotype up to 24 months of age
  (MGI Ref ID J:119741)

• paralysis
  • 44% of mutants exhibit paresis or paralysis and presence of a hunchback posture at 11 months of age
  (MGI Ref ID J:165441)
  • mice show paralysis at 7-10 months of age
  (MGI Ref ID J:119741)

• paresis
  • 44% of mutants exhibit paresis or paralysis and presence of a hunchback posture at 11 months of age
  (MGI Ref ID J:165441)

• weakness
  • limb grasping at 3 months of age is followed by limb weakness
  (MGI Ref ID J:119741)

growth/size/body region phenotype

• weight loss
  • slight decrease in weight is seen at 11 months of age
  (MGI Ref ID J:165441)

mortality/aging

• premature death
  (MGI Ref ID J:165441)
  • ~80% of mice die by 12 months of age, with median survival of ~9 months
  (MGI Ref ID J:119741)

muscle phenotype

• dystrophic muscle
  • affected muscles show group atrophies with small angular fibers, indicating chronic denervation of motor neurons
  (MGI Ref ID J:119741)

• progressive muscle weakness
  • mice show motor increasing weakness and neurogenic muscular atrophy after 3 months of age
  (MGI Ref ID J:119741)

nervous system phenotype

• abnormal amygdala morphology
  • neuron loss is observed at 12 months of age
  (MGI Ref ID J:119741)

• abnormal cerebral cortex morphology
  • at 3 months, mice have neurofilament light chain and tau-positive spheroids in the cerebral cortex
  (MGI Ref ID J:119741)
  • prominent atrophy of neocortex is observed at 9 months of age, with a 20% reduction in volume at 12 months of age
  (MGI Ref ID J:119741)

• abnormal CNS synaptic transmission
  • basal synaptic transmission is impaired at 6 months
  (MGI Ref ID J:119741)
  • mice show small fiber volley amplitude, fEPSP slopes and amplitudes at all stimulus intensities tested
  (MGI Ref ID J:119741)

• abnormal dentate gyrus morphology
  • at 3 months, mice have neurofilament light chain and tau-positive spheroids in the dentate gyrus, as well as in the cortex
  (MGI Ref ID J:119741)

• abnormal entorhinal cortex morphology
  • neuron loss is observed at 12 months of age
  (MGI Ref ID J:119741)

• abnormal excitatory postsynaptic potential
  • at 6 months, the maximum fEPSP is reduced relative to wild-type MAPT transgenic mice
  (MGI Ref ID J:119741)

• abnormal hippocampal mossy fiber morphology
  • at 3 months but not at 6 months, neurofilament light chain-positive mossy fibers are not detected in CA3 of hippocampus
  (MGI Ref ID J:119741)
  • at 3 months but not at 6 months, neurofilament light chain-positive mossy fibers are not detected in CA3 of hippocampus at 3 months but not at 6 months, neurofilament light chain-positive mossy fibers are not detected in CA3 of hippocampus
  (MGI Ref ID J:119741)

• abnormal hippocampus pyramidal cell morphology
  • significant reduction in number in the hippocampal CA3 region is found at 12 months of age, but no loss is detected at 6 months
  (MGI Ref ID J:119741)

• abnormal spinal cord white matter morphology
  • at 3 months, mice have neurofilament light chain and tau-positive spheroids in the spinal cord white matter
  (MGI Ref ID J:119741)

• astrocytosis
  • gliosis is striking at 6 months in the white matter where little tau pathology exists
  (MGI Ref ID J:119741)
  • microglial activation precedes astrogliosis in brain regions containing NFTs; this is found in the brain and spinal cord, especially in white matter at 3 months of age with increases seen at 6 months in white and gray matter of hippocampus, amygdala, entorhinal cortex and spinal cord
  (MGI Ref ID J:119741)
  • rhinal cortex and spinal cord
  (MGI Ref ID J:119741)
  • younger mice (3-4 months) show no overt gliosis but increased microglial activation is detected in the hippocampus
  (MGI Ref ID J:119741)

• brain atrophy
  • limb grasping at 3 months of age is followed by brain atrophy
  (MGI Ref ID J:119741)

• decreased hippocampus volume
  • ~25% and ~40% reductions in hippocampal volume at 9 and 12 months of age respectively
  (MGI Ref ID J:119741)

• decreased paired-pulse facilitation
  • at 6 months, mice show significantly reduce paired pulse facilitation (PPF) ratio at all stimulus intervals
  (MGI Ref ID J:119741)

• dilated brain ventricles
  • by 8 months of age, ventricular dilatation is seen
  (MGI Ref ID J:119741)

• hippocampal neuron degeneration
  (MGI Ref ID J:119741)

• hippocampus atrophy
  • marked hippocampal atrophy at 9 months of age
  (MGI Ref ID J:119741)

• loss of hippocampal neurons
  • up to 6 months, mice show no neuron loss, but by 8 months of age, neuron loss in the hippocampus is seen, becoming more severe in hippocampus, as well as amygdala, neocortex and entorhinal cortex by 12 months of age
  (MGI Ref ID J:119741)

• neurodegeneration
  • mice show progressive neurodegeneration starting at 1 month of age, as determined by increasing loss of synaptophysin immunoreactivity
  (MGI Ref ID J:119741)

• neurofibrillary tangles
  • at 6 months of age, neurofibrillary tangles (NFT) are evident in neocortex, amygdala, hippocampus, brain stem and spinal cord but none are found in mice expressing wild-type human MAPT up to 24 months of age
  (MGI Ref ID J:119741)
  • mutants develop ThS-positive neurofibrillary tangles
  (MGI Ref ID J:165441)

• reduced long term potentiation
  • LTP in CA1 region of hippocampus is significantly deteriorated, indicating attenuated postsynaptic responsiveness and compromised synaptic plasticity, but at 6 months no overt reduction in neuron number is detected
  (MGI Ref ID J:119741)

• tau protein deposits
  • aggregation of insoluble tau in the cortex and hippocampus
  (MGI Ref ID J:233816)
  • at 3 months of age, mutants and mice expressing wild-type transgenic human tau show weak perikaryal and dendritic tau staining mainly in hippocampus, amygdala, cortex, brain stem, and spinal cord; at 6 months, mutants show stronger tau-positive neuronal staining in the hippocampus, amygdala, and spinal cord but older mice expressing wild-type human tau protein show no increases up to 12 months
  (MGI Ref ID J:119741)
  • mutants exhibit progression in the distribution of abnormally phosphorylated tau from the entorhinal and neocortex, followed by involvement of the hippocampal formation and subcortical structures, to finally penetration of all layers of the neocortex
  (MGI Ref ID J:165441)
  • taining in the hippocampus, amygdala, and spinal cord but older mice expressing wild-type human tau protein show no increases up to 12 months
  (MGI Ref ID J:119741)
  • with aging, brains of mice have increasing levels of insoluble tau deposits composed mainly of transgenic human tau; decrease in solubility of tau is observed between 3 and 6 months
  (MGI Ref ID J:119741)