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Cited by 247Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeurological Disease Mechanisms and Treatments

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P301S Mutant Human Tau Transgenic Mice Manifest Early Symptoms of Human Tauopathies with Dementia and Altered Sensorimotor Gating

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Takeuchi, Hiroki, Iba, Michiyo, Inoue, Haruhisa, Higuchi, Makoto, Takao, Keizo, Tsukita, Kayoko, Karatsu, Yoshiko, Iwamoto, Yumiko, Miyakawa, Tsuyoshi, Suhara, Tetsuya, Trojanowski, John Q., Lee, Virginia M. -Y., Takahashi, Ryosuke·2011·PLoS ONE
DOI 10.1371/journal.pone.0021050PMC PMC3115982
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Abstract

Tauopathies are neurodegenerative disorders characterized by the accumulation of abnormal tau protein leading to cognitive and/or motor dysfunction. To understand the relationship between tau pathology and behavioral impairments, we comprehensively assessed behavioral abnormalities in a mouse tauopathy model expressing the human P301S mutant tau protein in the early stage of disease to detect its initial neurological manifestations. Behavioral abnormalities, shown by open field test, elevated plus-maze test, hot plate test, Y-maze test, Barnes maze test, Morris water maze test, and/or contextual fear conditioning test, recapitulated the neurological deficits of human tauopathies with dementia. Furthermore, we discovered that prepulse inhibition (PPI), a marker of sensorimotor gating, was enhanced in these animals concomitantly with initial neuropathological changes in associated brain regions. This finding provides evidence that our tauopathy mouse model displays neurofunctional abnormalities in prodromal stages of disease, since enhancement of PPI is characteristic of amnestic mild cognitive impairment, a transitional stage between normal aging and dementia such as Alzheimer's disease (AD), in contrast with attenuated PPI in AD patients. Therefore, assessment of sensorimotor gating could be used to detect the earliest manifestations of tauopathies exemplified by prodromal AD, in which abnormal tau protein may play critical roles in the onset of neuronal dysfunctions.

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Figures

Figure 1 Open field test in 13-week-old mice. Total distance traveled (A), vertical activity (B), center time (C), stereotypic counts (D). Tauopathy model mice traveled longer distance (F(1, 33) = 4.467, p = 0.0422, between groups, interaction between genotypes and time; F(1,23) = 1.955, p = 0.0049), showed more vertical activity in the latter half of the task (F(1, 33) = 4.382, p = 0.0441, between groups), spent more time in the center of the field (F(1, 33) = 4.239, p = 0.0475, between groups), significantly. No statistical significance was observed in stereotypic counts (F(1, 33) = 2.226, p = 0.1452, between groups). Controls: wild type mice (n = 19); Mutants: tauopathy model mice (n = 16). Tested with two-way mixed model ANOVA.
Figure 1 Open field test in 13-week-old mice. Total distance traveled (A), vertical activity (B), center time (C), stereotypic counts (D). Tauopathy model mice traveled longer distance (F(1, 33) = 4.467, p = 0.0422, between groups, interaction between genotypes and time; F(1,23) = 1.955, p = 0.0049), showed more vertical activity in the latter half of the task (F(1, 33) = 4.382, p = 0.0441, between groups), spent more time in the center of the field (F(1, 33) = 4.239, p = 0.0475, between groups), significantly. No statistical significance was observed in stereotypic counts (F(1, 33) = 2.226, p = 0.1452, between groups). Controls: wild type mice (n = 19); Mutants: tauopathy model mice (n = 16). Tested with two-way mixed model ANOVA.CC BY · PubMed Central
Figure 2 Elevated plus maze test. Number of total entries (A), percentage of entries into open arms (B), total distance traveled during the test (C), percentage of time on open arms (D). Percentages of entries into open arms and of time in open arms were significantly increased in tauopathy model mice, respectively. Three wild type mice and 2 tauopathy model mice dropped from the open arms and failed to complete the task. Controls: wild type mice (n = 16); Mutants: tauopathy model mice (n = 15). Tested with Student's t-test.
Figure 2 Elevated plus maze test. Number of total entries (A), percentage of entries into open arms (B), total distance traveled during the test (C), percentage of time on open arms (D). Percentages of entries into open arms and of time in open arms were significantly increased in tauopathy model mice, respectively. Three wild type mice and 2 tauopathy model mice dropped from the open arms and failed to complete the task. Controls: wild type mice (n = 16); Mutants: tauopathy model mice (n = 15). Tested with Student's t-test.CC BY · PubMed Central
Figure 3 Porsolt forced swim test. Percentage of each minute immobilized (A), distance traveled during the test (B). In the 6th block of Day 1, immobility was decreased (two-way mixed model ANOVA, F(1, 33) = 6.607, p = 0.0149) and distance traveled was increased in tauopathy model mice (two-way mixed model ANOVA, F(1, 33) = 7.308, p = 0.0108). In general, no statistical significance was observed, tested with two-way mixed model ANOVA (immobility: Day 1, F(1, 33) = 3.958, p = 0.055, between groups. Day 2, F(1, 33) = 2.246, p = 0.1434, between groups; distance traveled: Day 1, F(1, 33) = 0.324, p = 0.5733, between groups. Day 2, F(1, 33) = 0.915, p = 0.3458, between groups). Controls: wild type mice (n = 19); Mutants: tauopathy model mice (n = 16).
Figure 3 Porsolt forced swim test. Percentage of each minute immobilized (A), distance traveled during the test (B). In the 6th block of Day 1, immobility was decreased (two-way mixed model ANOVA, F(1, 33) = 6.607, p = 0.0149) and distance traveled was increased in tauopathy model mice (two-way mixed model ANOVA, F(1, 33) = 7.308, p = 0.0108). In general, no statistical significance was observed, tested with two-way mixed model ANOVA (immobility: Day 1, F(1, 33) = 3.958, p = 0.055, between groups. Day 2, F(1, 33) = 2.246, p = 0.1434, between groups; distance traveled: Day 1, F(1, 33) = 0.324, p = 0.5733, between groups. Day 2, F(1, 33) = 0.915, p = 0.3458, between groups). Controls: wild type mice (n = 19); Mutants: tauopathy model mice (n = 16).CC BY · PubMed Central
Figure 4 Prepulse inhibition test. Startle amplitude (A), percentage of prepulse inhibition (B). Tauopathy model mice had lower startle amplitudes than wild type mice at both 110 dB and 120 dB, statistically significant at 120 dB. Percent PPI was significantly greater in tauopathy model mice. Controls: wild type mice (n = 19); Mutants: tauopathy model mice (n = 16). Tested with Mann-Whitney's U-test in startle amplitude 110 dB, the others with Student's t-test.
Figure 4 Prepulse inhibition test. Startle amplitude (A), percentage of prepulse inhibition (B). Tauopathy model mice had lower startle amplitudes than wild type mice at both 110 dB and 120 dB, statistically significant at 120 dB. Percent PPI was significantly greater in tauopathy model mice. Controls: wild type mice (n = 19); Mutants: tauopathy model mice (n = 16). Tested with Mann-Whitney's U-test in startle amplitude 110 dB, the others with Student's t-test.CC BY · PubMed Central
Figure 5 Y-maze test. Number of total entries (A), number of total alternations (B), total distance traveled (C), percentage of alternations (D). In tauopathy model mice, significantly increased numbers of total entries and total alternations, and prolonged distance traveled were observed. Percentage of alternations was significantly decreased, suggesting that short-term memory was impaired in tauopathy model mice. Controls: wild type mice (n = 19); Mutants: tauopathy model mice (n = 16). Tested with Mann-Whitney's U-test in % alternation, the others with Student's t-test.
Figure 5 Y-maze test. Number of total entries (A), number of total alternations (B), total distance traveled (C), percentage of alternations (D). In tauopathy model mice, significantly increased numbers of total entries and total alternations, and prolonged distance traveled were observed. Percentage of alternations was significantly decreased, suggesting that short-term memory was impaired in tauopathy model mice. Controls: wild type mice (n = 19); Mutants: tauopathy model mice (n = 16). Tested with Mann-Whitney's U-test in % alternation, the others with Student's t-test.CC BY · PubMed Central
Figure 6 Crawley's social interaction test. The 1st trial with one-stranger mouse (A–D, I, J), the 2nd trial with one-familiar mouse and one-stranger mouse (E–H, K, L). Time spent in each chamber was tested with one-way ANOVA, followed by Fisher's least significant difference method as post hoc analysis within groups, with Student's t-test between groups. Time spent in each cage (mouse with no prior contact with a subject mouse) was analyzed by Student's t-test and Welch's t-test. In the 1st trial, both groups spent more time in the chamber (A, B) and the cage (C, D) of the stranger side. In the 2nd trial, no statistical significance was observed between the time spent in the stranger and familiar chambers of the two groups (Controls: p = 0.7166; Mutants: p = 0.2116, Controls vs Mutants: Stranger side: p = 0.5308, Empty side: p = 0.4412). Control wild type mice showed significantly more time spent with stranger mice (G, Controls vs Mutants: p = 0.03761 (Welch's t-test), Familiar side: p = 0.04053 (Student's t-test)). However, tauopathy model mice tended to spend more time with familiar mice (H). Controls: wild type mice (n = 19); Mutants: tauopathy model mice (n = 16).
Figure 6 Crawley's social interaction test. The 1st trial with one-stranger mouse (A–D, I, J), the 2nd trial with one-familiar mouse and one-stranger mouse (E–H, K, L). Time spent in each chamber was tested with one-way ANOVA, followed by Fisher's least significant difference method as post hoc analysis within groups, with Student's t-test between groups. Time spent in each cage (mouse with no prior contact with a subject mouse) was analyzed by Student's t-test and Welch's t-test. In the 1st trial, both groups spent more time in the chamber (A, B) and the cage (C, D) of the stranger side. In the 2nd trial, no statistical significance was observed between the time spent in the stranger and familiar chambers of the two groups (Controls: p = 0.7166; Mutants: p = 0.2116, Controls vs Mutants: Stranger side: p = 0.5308, Empty side: p = 0.4412). Control wild type mice showed significantly more time spent with stranger mice (G, Controls vs Mutants: p = 0.03761 (Welch's t-test), Familiar side: p = 0.04053 (Student's t-test)). However, tauopathy model mice tended to spend more time with familiar mice (H). Controls: wild type mice (n = 19); Mutants: tauopathy model mice (n = 16).CC BY · PubMed Central
Figure 7 Morris water maze test. Training session (A, B), probe test 24 h after the last (6th) training (C–G). No statistical significances were observed in the training session with the visible platform (A, F(1,46) = 0.0395, p = 0.8434, between groups), but tauopathy model mice spent significantly more time to find the invisible platform (B, F(1,46) = 11.2326, p = 0.0016, between groups). Tested by two-way mixed model ANOVA. In the probe trial, tauopathy model mice showed less time (C, p<0.0001) and path length (D, p<0.0001) in the pool quadrant where the platform had previously been placed, and smaller numbers of target platform crossings (E, p<0.0001). No statistical significance was observed in total path length (F, p>0.05) and swimming speed (G, p>0.05) between the two groups of mice. Controls: wild type mice (n = 11); Mutants: tauopathy model mice (n = 29). Tested with Student's t-test.
Figure 7 Morris water maze test. Training session (A, B), probe test 24 h after the last (6th) training (C–G). No statistical significances were observed in the training session with the visible platform (A, F(1,46) = 0.0395, p = 0.8434, between groups), but tauopathy model mice spent significantly more time to find the invisible platform (B, F(1,46) = 11.2326, p = 0.0016, between groups). Tested by two-way mixed model ANOVA. In the probe trial, tauopathy model mice showed less time (C, p<0.0001) and path length (D, p<0.0001) in the pool quadrant where the platform had previously been placed, and smaller numbers of target platform crossings (E, p<0.0001). No statistical significance was observed in total path length (F, p>0.05) and swimming speed (G, p>0.05) between the two groups of mice. Controls: wild type mice (n = 11); Mutants: tauopathy model mice (n = 29). Tested with Student's t-test.CC BY · PubMed Central
Figure 8 Fear conditioning test. Percentage of freezing time of each minute of conditioning (A), context testing (B), cued testing with altered context (C). Freezing tended to be reduced in tauopathy model mice in context testing. In the 4th block, freezing was significantly decreased (two-way mixed model ANOVA, F(1, 33) = 5.479, p = 0.0254). In general, no statistical significance was observed as tested with two-way mixed model ANOVA (Conditioning: F(1, 33) = 0.006, p = 0.9378, between groups; Context testing: F(1, 33) = 3.000, p = 0.0926, between groups; Cued testing: F(1, 33) = 0.771, p = 0.3863, between groups). Controls: wild type mice (n = 19); Mutants: tauopathy model mice (n = 16).
Figure 8 Fear conditioning test. Percentage of freezing time of each minute of conditioning (A), context testing (B), cued testing with altered context (C). Freezing tended to be reduced in tauopathy model mice in context testing. In the 4th block, freezing was significantly decreased (two-way mixed model ANOVA, F(1, 33) = 5.479, p = 0.0254). In general, no statistical significance was observed as tested with two-way mixed model ANOVA (Conditioning: F(1, 33) = 0.006, p = 0.9378, between groups; Context testing: F(1, 33) = 3.000, p = 0.0926, between groups; Cued testing: F(1, 33) = 0.771, p = 0.3863, between groups). Controls: wild type mice (n = 19); Mutants: tauopathy model mice (n = 16).CC BY · PubMed Central
Figure 9 Representative immunofluorescence histological findings of tauopathy model mice and wild type mice. Male mice 4 months of age: Tauopathy model mice (A–D), and wild type mice (E–H). Lateral globus pallidus (A, E), anterior cortical amygdaloid nucleus (B, F), auditory cortex (C, G), and ventral hippocampus (CA3; D, H). Scale Bar: 100 µm.
Figure 9 Representative immunofluorescence histological findings of tauopathy model mice and wild type mice. Male mice 4 months of age: Tauopathy model mice (A–D), and wild type mice (E–H). Lateral globus pallidus (A, E), anterior cortical amygdaloid nucleus (B, F), auditory cortex (C, G), and ventral hippocampus (CA3; D, H). Scale Bar: 100 µm.CC BY · PubMed Central
Figure 10 Representative immunoblotting of the whole cortex (A) and the whole hippocampus (B) of mice at the age of 6 months, after the comprehensive behavioral analysis. Phosphorylated tau was observed in the brains of tauopathy model mice, both in the cortex and in the hippocampus, but not in those of control mice. Each 5 samples were randomly selected.
Figure 10 Representative immunoblotting of the whole cortex (A) and the whole hippocampus (B) of mice at the age of 6 months, after the comprehensive behavioral analysis. Phosphorylated tau was observed in the brains of tauopathy model mice, both in the cortex and in the hippocampus, but not in those of control mice. Each 5 samples were randomly selected.CC BY · PubMed Central

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Metadata

Authors
Takeuchi, H., Iba, M., Inoue, H., Higuchi, M., Takao, K., Tsukita, K., Karatsu, Y., Iwamoto, Y., Miyakawa, T., Suhara, T., Trojanowski, J. Q., Lee, V. M. Y., & Takahashi, R.
Affiliations
  • Kyoto University (JP)
  • Hospital of the University of Pennsylvania (US)
  • National Institute of Radiological Sciences (JP)
  • National Institute for Physiological Sciences (JP)
  • Fujita Health University (JP)
Corresponding author
Inoue, Haruhisa
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2011-06-15
Volume
6
Issue
6
Pages
e21050
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0021050
PMC
PMC3115982
OpenAlex
W2158765009
Cited by
247
References
65
Citations by year
2026: 27 · 2025: 36 · 2024: 24 · 2023: 18 · 2022: 24 · 2021: 24 · 2020: 21 · 2019: 13 · 2018: 7 · 2017: 11 · 2016: 9 · 2015: 11 · 2014: 13 · 2013: 5 · 2012: 3
FWCI
4.80
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Institutional Repositories DataBase (IRDB) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
  • Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
  • QST-Repository (National Institutes for Quantum and Radiological Science and Technology) (submittedVersion)
  • Kyoto University Research Information Repository (Kyoto University) (submittedVersion, cc-by)
Funders
  • National Institutes of Health (AG 10 124)
  • Japan Society for the Promotion of Science (22700338, 23390235, 21300121)
  • Japan Science and Technology Agency
  • RIKEN
  • National Institute on Aging (P30AG010124, P01AG017586, AG17586, AG-10124)
  • RIKEN Brain Science Institute
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
tauopathy, transgenic mouse model, dementia, sensorimotor gating, prepulse inhibition, prodromal Alzheimer's disease, amnestic mild cognitive impairment, behavioral abnormalities, early disease detection, cognitive impairment
MeSH terms
Animals, Dementia, Disease Models, Animal, Humans, Mice, Transgenic, tau Proteins, Maze Learning, Mice, Sensory Gating

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