Pathogenic Tau Impairs Axon Initial Segment Plasticity and Excitability Homeostasis

Peter Dongmin Sohn, Cindy Tzu Ling Huang, Rui Yan, Li Fan, Tara E. Tracy, Carolina M. Camargo, Kelly M. Montgomery, Taylor Arhar, Sue Ann Mok, Rebecca Freilich, Justin Baik, Manni He, Shiaoching Gong, Erik D. Roberson, Celeste M. Karch, Jason E. Gestwicki, Ke Xu, Kenneth S. Kosik, Li Gan

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Dysregulation of neuronal excitability underlies the pathogenesis of tauopathies, including frontotemporal dementia (FTD) with tau inclusions. A majority of FTD-causing tau mutations are located in the microtubule-binding domain, but how these mutations alter neuronal excitability is largely unknown. Here, using CRISPR/Cas9-based gene editing in human pluripotent stem cell (iPSC)-derived neurons and isogenic controls, we show that the FTD-causing V337M tau mutation impairs activity-dependent plasticity of the cytoskeleton in the axon initial segment (AIS). Extracellular recordings by multi-electrode arrays (MEAs) revealed that the V337M tau mutation in human neurons leads to an abnormal increase in neuronal activity in response to chronic depolarization. Stochastic optical reconstruction microscopy of human neurons with this mutation showed that AIS plasticity is impaired by the abnormal accumulation of end-binding protein 3 (EB3) in the AIS submembrane region. These findings expand our understanding of how FTD-causing tau mutations dysregulate components of the neuronal cytoskeleton, leading to network dysfunction.

Original languageEnglish
Pages (from-to)458-470.e5
JournalNeuron
Volume104
Issue number3
DOIs
StatePublished - Nov 6 2019

Keywords

  • EB3
  • FTD
  • axon initial segment
  • cytoskeleton
  • homeostasis
  • neuronal activity
  • tau

Fingerprint Dive into the research topics of 'Pathogenic Tau Impairs Axon Initial Segment Plasticity and Excitability Homeostasis'. Together they form a unique fingerprint.

  • Cite this

    Sohn, P. D., Huang, C. T. L., Yan, R., Fan, L., Tracy, T. E., Camargo, C. M., Montgomery, K. M., Arhar, T., Mok, S. A., Freilich, R., Baik, J., He, M., Gong, S., Roberson, E. D., Karch, C. M., Gestwicki, J. E., Xu, K., Kosik, K. S., & Gan, L. (2019). Pathogenic Tau Impairs Axon Initial Segment Plasticity and Excitability Homeostasis. Neuron, 104(3), 458-470.e5. https://doi.org/10.1016/j.neuron.2019.08.008