Cognition and hippocampal synaptic plasticity in mice with a homozygous tau deletion
Abstract
Tau has been implicated in the organization, stabilization, and dynamics of microtubules. In Alzheimer's disease and more than 20 neurologic disorders tau missorting, hyperphosphorylation, and aggregation is a hallmark. They are collectively referred to as tauopathies. Although the impact of human tauopathies on cognitive processes has been explored in transgenic mouse models, the functional consequences of tau deletion on cognition are far less investigated. Here, we subjected tau knock-out (KO) mice to a battery of neurocognitive, behavioral, and electrophysiological tests. Although KO and wild-type mice were indistinguishable in motor abilities, exploratory and anxiety behavior, KO mice showed impaired contextual and cued fear conditioning. In contrast, extensive spatial learning in the water maze resulted in better performance of KO mice during acquisition. In electrophysiological experiments, basal synaptic transmission and paired-pulse facilitation in the hippocampal CA1-region were unchanged. Interestingly, deletion of tau resulted in severe deficits in long-term potentiation but not long-term depression. Our results suggest a role of tau in certain cognitive functions and implicate long-term potentiation as the relevant physiological substrate.
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Tau-mediated neurodegeneration arises from multiple pathological mechanisms including loss of normal function, gain of toxic function, aggregation, and mislocalization.
“Tau-mediated neurodegeneration arises from multiple pathological mechanisms, including loss of normal function [37–42], gain of toxic function [43–46], aggregation [44, 47–49], and mislocalization [50–52].”
From Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease (2026) · cites this paper as [38]
The literature has established a role for tau in regulating glutamatergic synaptic function, where it interacts with Fyn, NMDARs, PSD-95, and SynGAP1.
“The literature has established a role for tau in regulating glutamatergic synaptic function, where it interacts with Fyn, NMDARs, PSD-95, and SynGAP1 [41, 77, 105].”
From Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease (2026) · cites this paper as [105]
Dendritic tau may regulate synaptic plasticity; synaptic activity can recruit tau to postsynaptic densities, and tau deletion in various mouse models shows deficits in LTP or LTD.
“Dendritic tau may also play a role in regulating synaptic plasticity, as synaptic activity can recruit tau to the postsynaptic densities, where tau deletion in various mouse models show deficits either in LTP or LTD [129, 131, 132].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [131]
Cites
Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning.
Phillips, R. G., & LeDoux, J. E. (1992) · Behavioral Neuroscience · doi:10.1037/0735-7044.106.2.274 · Cited by 3,292 · see citing works
Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning.
Phillips, R. G., & LeDoux, J. E. (1992) · Behavioral Neuroscience · doi:10.1037//0735-7044.106.2.274 · Cited by 3,262 · see citing works
A protein factor essential for microtubule assembly
Weingarten, M. D., Lockwood, A. H., Hwo, S. Y., & Kirschner, M. W. (1975) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.72.5.1858 · Cited by 3,089 · see citing works
Synaptic Plasticity and Memory: An Evaluation of the Hypothesis
Martin, S. J., Grimwood, P. D., & Morris, R. G. M. (2000) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.23.1.649 · Cited by 2,794 · see citing works
Buée, L., Bussière, T., Buée‐Scherrer, V., Delacourte, A., & Hof, P. R. (2000) · Brain Research Reviews · doi:10.1016/s0165-0173(00)00019-9 · Cited by 2,007 · see citing works
Learning induces long-term potentiation in the hippocampus
Whitlock, J. R., Heynen, A. J., Shuler, M. G., & Bear, M. F. (2006) · Science · doi:10.1126/science.1128134 · Cited by 1,913 · see citing works
Reducing Endogenous Tau Ameliorates Amyloid ß-Induced Deficits in an Alzheimer's Disease Mouse Model
Roberson, E. D., Scearce-Levie, K., Palop, J. J., Yan, F., Cheng, I. H., Wu, T., Gerstein, H., Yu, G.-Q., & Mucke, L. (2007) · Science · doi:10.1126/science.1141736 · Cited by 1,892 · see citing works
Dendritic Function of Tau Mediates Amyloid-β Toxicity in Alzheimer's Disease Mouse Models
Ittner, L. M., Ke, Y. D., Delerue, F., Bi, M., Gladbach, A., van Eersel, J., Wölfing, H., Chieng, B. C., Christie, M. J., Napier, I. A., et al. (2010) · Cell · doi:10.1016/j.cell.2010.06.036 · Cited by 1,821 · see citing works
Altered microtubule organization in small-calibre axons of mice lacking tau protein
Harada, A., Oguchi, K., Okabe, S., Kuno, J., Terada, S., Ohshima, T., Sato-Yoshitake, R., Takei, Y., Noda, T., & Hirokawa, N. (1994) · Nature · doi:10.1038/369488a0 · Cited by 806 · see citing works
Long-Term Depression in Hippocampus
Bear, M. F., & Abraham, W. C. (1996) · Annual Review of Neuroscience · doi:10.1146/annurev.ne.19.030196.002253 · Cited by 601 · see citing works
Inhibition of neuronal maturation in primary hippocampal neurons from tau deficient mice
Dawson, H. N., Ferreira, A., Eyster, M. V., Ghoshal, N., Binder, L. I., & Vitek, M. P. (2001) · Journal of Cell Science · doi:10.1242/jcs.114.6.1179 · Cited by 527 · see citing works
Neurotrophins are required for nerve growth during development
Tucker, K. L., Meyer, M., & Barde, Y. (2001) · Nature Neuroscience · doi:10.1038/82868 · Cited by 526 · see citing works
Probing the biology of Alzheimer’s disease in mice
Ashe, K. H., & Zahs, K. R. (2010) · Neuron · doi:10.1016/j.neuron.2010.04.031 · Cited by 413 · see citing works
Is Heterosynaptic modulation essential for stabilizing hebbian plasiticity and memory
Bailey, C. H., Giustetto, M., Huang, Y.-Y., Hawkins, R. D., & Kandel, E. R. (2000) · Nature Reviews Neuroscience · doi:10.1038/35036191 · Cited by 382 · see citing works
Tau pathophysiology in neurodegeneration: a tangled issue
Spires‐Jones, T. L., Stoothoff, W. H., de Calignon, A., Jones, P., & Hyman, B. T. (2009) · Trends in Neurosciences · doi:10.1016/j.tins.2008.11.007 · Cited by 316 · see citing works
Tau Protein Is Required for Amyloid β-Induced Impairment of Hippocampal Long-Term Potentiation
Shipton, O. A., Leitz, J. R., Dworzak, J., Acton, C. E. J., Tunbridge, E. M., Denk, F., Dawson, H. N., Vitek, M. P., Wade-Martins, R., Paulsen, O., et al. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.2610-10.2011 · Cited by 315 · see citing works
Microtubule-associated protein tau is essential for long-term depression in the hippocampus
Kimura, T., Whitcomb, D. J., Jo, J., Regan, P., Piers, T., Heo, S., Brown, C., Hashikawa, T., Murayama, M., Seok, H., et al. (2014) · Philosophical Transactions of the Royal Society B: Biological Sciences · doi:10.1098/rstb.2013.0144 · Cited by 307 · see citing works
Biochemistry of Tau in Alzheimer’s disease and related neurological disorders
Sergeant, N., Bretteville, A., Hamdane, M., Caillet-Boudin, M.-L., Grognet, P., Bombois, S., Blum, D., Delacourte, A., Pasquier, F., Vanmechelen, E., et al. (2008) · Expert Review of Proteomics · doi:10.1586/14789450.5.2.207 · Cited by 300 · see citing works
Self-citationBalschun, D., Wolfer, D. P., Gass, P., Mantamadiotis, T., Welzl, H., Schütz, G., Frey, J. U., & Lipp, H.-P. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-15-06304.2003 · Cited by 229 · see citing works
Self-citationMuscle weakness, hyperactivity, and impairment in fear conditioning in tau-deficient mice
Ikegami, S. (2000) · Neuroscience Letters · doi:10.1016/s0304-3940(99)00964-7 · Cited by 221 · see citing works
Phosphorylation of tau regulates its axonal transport by controlling its binding to kinesin
Cuchillo‐Ibáñez, I., Seereeram, A., Byers, H. L., Leung, K., Ward, M. A., Anderton, B. H., & Hanger, D. P. (2008) · The FASEB Journal · doi:10.1096/fj.08-109181 · Cited by 170 · see citing works
Boekhoorn, K., Terwel, D., Biemans, B. A. M., Borghgraef, P., Wiegert, O., Ramakers, G. J. A., de Vos, K., Krugers, H. J., Tomiyama, T., Mori, H., et al. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.5425-05.2006 · Cited by 167 · see citing works
Evidence That Long-Term Potentiation Occurs within Individual Hippocampal Synapses during Learning
Fedulov, V., Rex, C. S., Simmons, D. A., Palmer, L. C., Gall, C. M., & LYNCH, G. S. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.2003-07.2007 · Cited by 150 · see citing works
Loss of tau elicits axonal degeneration in a mouse model of Alzheimer's disease
Dawson, H. N., Cantillana, V., Jansen, M., Wang, H., Vitek, M. P., Wilcock, D. M., Lynch, J., & Laskowitz, D. T. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2010.04.037 · Cited by 137 · see citing works
Knock-out and transgenic mouse models of tauopathies
Denk, F., & Wade‐Martins, R. (2007) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.05.010 · Cited by 120 · see citing works
Age-appropriate cognition and subtle dopamine-independent motor deficits in aged Tau knockout mice
Morris, M., Hamto, P., Adame, A., Devidze, N., Masliah, E., & Mucke, L. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.12.003 · Cited by 117 · see citing works
When Are Class I Metabotropic Glutamate Receptors Necessary for Long-Term Potentiation?
Wilsch, V. W., Behnisch, T., Jäger, T., Reymann, K. G., & Balschun, D. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-16-06071.1998 · Cited by 116 · see citing works
Self-citationder Jeugd, A. V., Ahmed, T., Burnouf, S., Bélarbi, K., Hamdame, M., Grosjean, M., Humez, S., Balschun, D., Blum, D. L., Buée, L., et al. (2010) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2010.12.005 · Cited by 98 · see citing works
Self-citationDubey, M., Chaudhury, P., Kabiru, H., & Shea, T. B. (2007) · Cell Motility and the Cytoskeleton · doi:10.1002/cm.20243 · Cited by 91 · see citing works
Meiri, N., Sun, M., Segal, Z., & Alkon, D. L. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.25.15037 · Cited by 79 · see citing works
Burnouf, S., Martire, A., Derisbourg, M. J., Laurent, C., Bélarbi, K., Leboucher, A., Fernández-Gómez, F.-J., Troquier, L., Eddarkaoui, S., Grosjean, M., et al. (2012) · Aging Cell · doi:10.1111/acel.12018 · Cited by 77 · see citing works
Self-citationGoddyn, H., Leo, S., Meert, T. F., & DHOOGE, R. (2006) · Behavioural Brain Research · doi:10.1016/j.bbr.2006.06.016 · Cited by 76 · see citing works
Self-citationD’Hooge, R., Lüllmann‐Rauch, R., Beckers, T., Balschun, D., Schwake, M., Reiß, K., FIGURA, K. V., & Säftig, P. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.0283-05.2005 · Cited by 68 · see citing works
Self-citationSynaptic Plasticity and Memory
El-Gaby, M., Shipton, O. A., & Paulsen, O. (2014) · The Neuroscientist · doi:10.1177/1073858414550658 · Cited by 62 · see citing works
Lo, A. C., Iscru, E., Blum, D. L., Tesseur, I. C., Callaerts‐Vegh, Z., Buée, L., Strooper, B. D., Balschun, D., & D’Hooge, R. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-122296 · Cited by 34 · see citing works
Self-citationAhmed, T., Sabanov, V., D’Hooge, R., & Balschun, D. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.04.006 · Cited by 19 · see citing works
Self-citationConditionally inducible tau mice – designing a better mouse model of neurodegenerative diseases
Janus, C. (2008) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2007.00375.x · Cited by 15 · see citing works
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Roles of tau protein in health and disease
Guo, T., Noble, W., & Hanger, D. P. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1707-9 · Cited by 1,003 · see citing works
Arendt, T., Stieler, J. T., & Holzer, M. (2016) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2016.08.018 · Cited by 609 · see citing works
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Chang, C.-W., Shao, E., & Mucke, L. (2021) · Science · doi:10.1126/science.abb8255 · Cited by 263 · see citing works
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Gao, Y.-L., Wang, N., Sun, F.-R., Cao, X.-P., Zhang, W., & Yu, J.-T. (2018) · Annals of Translational Medicine · doi:10.21037/atm.2018.04.23 · Cited by 222 · see citing works
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Sinsky, J., Pichlerova, K., & Hanes, J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22179207 · Cited by 220 · see citing works
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Toral-Rios, D., Pichardo-Rojas, P. S., Alonso-Vanegas, M., & Campos-Peña, V. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00019 · Cited by 158 · see citing works
Loss of tau rescues inflammation-mediated neurodegeneration
Maphis, N., Xu, G., Kokiko-Cochran, O. N., Cardona, A. E., Ransohoff, R. M., Lamb, B. T., & Bhaskar, K. (2015) · Frontiers in Neuroscience · doi:10.3389/fnins.2015.00196 · Cited by 91 · see citing works
Persistent repression of tau in the brain using engineered zinc finger protein transcription factors
Wegmann, S., DeVos, S. L., Zeitler, B., Marlen, K., Bennett, R. E., Perez-Rando, M., MacKenzie, D., Yu, Q., Commins, C., Bannon, R. N., et al. (2021) · Science Advances · doi:10.1126/sciadv.abe1611 · Cited by 77 · see citing works
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- Authors
- Ahmed, T., Van der Jeugd, A., Blum, D., Galas, M.-C., D’Hooge, R., Buee, L., & Balschun, D.
- Affiliations
- UCLouvain (BE)
- Inserm (FR)
- Corresponding author
- Balschun, Detlef
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2014-11
- Volume
- 35
- Issue
- 11
- Pages
- 2474-2478
- ISSN
- 0197-4580 (ISSN-L)
- OpenAlex
- W2069554147
- Cited by
- 137
- References
- 37
- Citations by year
- 2026: 9 · 2025: 8 · 2024: 6 · 2023: 8 · 2022: 15 · 2021: 19 · 2020: 14 · 2019: 15 · 2018: 14 · 2017: 6 · 2016: 13 · 2015: 6 · 2014: 4
- FWCI
- 6.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- Lirias (KU Leuven) (submittedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Funders
- FWO-Vlaanderen (G.0327.08)
- National institute of Health and Medical Research
- CNRS
- IMPRT
- Région Nord/Pas-de-Calais
- Fonds européen de développement économique et régional
- France Alzheimer
- Agence Nationale de la Recherche
- LECMA
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- tau knockout mice, hippocampal synaptic plasticity, long-term potentiation, long-term depression, fear conditioning, spatial learning, cognitive impairment, tauopathy, Alzheimer's disease, hippocampal CA1, paired-pulse facilitation, synaptic transmission
- MeSH terms
- Animals, Cognition, Disease Models, Animal, Hippocampus, Homozygote, Male, Mice, Inbred C57BL, Microtubules, Synaptic Transmission, Neuronal Plasticity, tau Proteins, Gene Deletion, Long-Term Potentiation, Mice, Knockout, Tauopathies, Spatial Learning
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