Hyperphosphorylated tau causes reduced hippocampal CA1 excitability by relocating the axon initial segment

Area of Science:

• Neuroscience
• Cell Biology
• Genetics

Background:

• Hyperphosphorylated tau is implicated in neurodegenerative tauopathies like Alzheimer's disease.
• Previous studies linked tau accumulation to memory deficits but not directly to reduced neuronal excitability.

Purpose of the Study:

• To investigate the role of hyperphosphorylated tau in reducing neuronal excitability.
• To elucidate the underlying mechanisms of tau-induced hyperexcitability in the hippocampus.

Main Methods:

• Utilized P301L tau transgenic mouse models and primary hippocampal neuronal cultures.
• Employed mutagenesis, pharmacological stabilization, and analysis of the axon initial segment (AIS) localization.
• Measured action potential initiation threshold and neuronal firing rates.

Main Results:

• Demonstrated that hyperphosphorylated tau depolarizes the action potential threshold and reduces firing in hippocampal CA1 neurons.
• Revealed that tau hyperphosphorylation causes a distal relocalization of the AIS, dependent on tau phosphorylation and microtubules.
• Showed that pharmacological stabilization prevented these structural and functional deficits.
• Observed that AIS is further down the axon in tau transgenic mice, correlating with reduced excitability.

Conclusions:

• Hyperphosphorylated tau reduces neuronal excitability through a mechanism involving the distal relocalization of the AIS.
• This tau-mediated AIS shift contributes to hippocampal dysfunction in tauopathies.
• Targeting tau phosphorylation or AIS stability may offer therapeutic strategies for tauopathies.