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Pathogenic Tau Impairs Axon Initial Segment Plasticity and Excitability Homeostasis.

TitlePathogenic Tau Impairs Axon Initial Segment Plasticity and Excitability Homeostasis.
Publication TypeJournal Article
Year of Publication2019
AuthorsSohn PDongmin, Huang CTzu-Ling, Yan R, Fan L, Tracy TE, Camargo CM, Montgomery KM, Arhar T, Mok S-A, Freilich R, Baik J, He M, Gong S, Roberson ED, Karch CM, Gestwicki JE, Xu K, Kosik KS, Gan L
JournalNeuron
Volume104
Issue3
Pagination458-470.e5
Date Published2019 Nov 06
ISSN1097-4199
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.

DOI10.1016/j.neuron.2019.08.008
Alternate JournalNeuron
PubMed ID31542321
PubMed Central IDPMC6880876
Grant ListU54 NS100717 / NS / NINDS NIH HHS / United States
R01 NS059690 / NS / NINDS NIH HHS / United States
K01 AG057862 / AG / NIA NIH HHS / United States
K01 AG046374 / AG / NIA NIH HHS / United States
R01 AG051390 / AG / NIA NIH HHS / United States
R01 AG054214 / AG / NIA NIH HHS / United States
C06 RR018928 / RR / NCRR NIH HHS / United States