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Neuron. 2019 Nov 6;104(3):458-470.e5. doi: 10.1016/j.neuron.2019.08.008. Epub 2019 Sep 18.

Pathogenic Tau Impairs Axon Initial Segment Plasticity and Excitability Homeostasis.

Author information

1
Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
2
Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA.
3
Helen and Robert Appel Alzheimer's Disease Research Institute, Weill Cornell Medical Center, New York, NY10021, USA.
4
Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.
5
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
6
Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
7
Department of Physics, University of California, Berkeley, Berkeley, CA 94720, USA.
8
Departments of Neurology and Neurobiology, University of Alabama, Birmingham, Birmingham, AL 35294, USA.
9
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.
10
Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: lig2033@med.cornell.edu.

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.

KEYWORDS:

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

PMID:
31542321
PMCID:
PMC6880876
[Available on 2020-11-06]
DOI:
10.1016/j.neuron.2019.08.008

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