Pathogenic Tau Impairs Axon Initial Segment Plasticity and Excitability Homeostasis

Area of Science:

• Neuroscience
• Cell Biology
• Genetics

Background:

• Neuronal excitability dysregulation is central to tauopathies like frontotemporal dementia (FTD).
• Most FTD-linked tau mutations reside in the microtubule-binding domain, yet their impact on neuronal excitability remains unclear.

Purpose of the Study:

• To investigate how the V337M tau mutation, associated with FTD, affects neuronal excitability and cytoskeletal dynamics in the axon initial segment (AIS).

Main Methods:

• CRISPR/Cas9 gene editing in human pluripotent stem cell (iPSC)-derived neurons.
• Extracellular recordings using multi-electrode arrays (MEAs).
• Stochastic optical reconstruction microscopy (STORM).

Main Results:

• The V337M tau mutation caused increased neuronal activity in human neurons under chronic depolarization.
• AIS plasticity was impaired in neurons with the V337M tau mutation.
• Abnormal accumulation of end-binding protein 3 (EB3) in the AIS submembrane region was observed.

Conclusions:

• FTD-associated tau mutations disrupt AIS cytoskeletal plasticity, contributing to neuronal network dysfunction.
• The V337M tau mutation impairs the dynamic regulation of the AIS cytoskeleton, impacting neuronal function.