Neuronal Hyperactivity Induces Tau Phosphorylation Selectively in Excitatory Pyramidal Neurons Which Contributes to GluA2 Regulation

Topic: Disease mechanisms in lab and animal studies

While tau plays a role in regulating neuronal network excitability, a process thought to be dysregulated in Alzheimer’s disease (AD), the molecular mechanisms linking tau and hyperexcitability remain unclear. To investigate interactions between endogenous tau and neuronal activity, we increased neuronal activity using bicuculline or suppressed activity using tetrodotoxin for 24 hours in rat hippocampal neurons. Chronic neuronal hyperactivity increased dendritic tau phosphorylation at S202/T205. This response was observed only in excitatory CA1 and CA3 pyramidal neurons, but not in inhibitory or dentate granule neurons. Dendritic phospho-tau positively correlated with neuronal activation after bicuculline treatment, as measured by cfos expression, and was prevented with inhibition of protein kinase A (PKA). To examine the functional consequences of tau S202/T205 phosphorylation, hippocampal neurons were transfected with wild-type tau or tau containing mutations preventing phosphorylation at these sites. Wildtype tau overexpression increased tau phosphorylation and reduced neuronal surface GluA2, which was prevented by phospho-site mutation. Extending these findings to mice, chronic low-dose picrotoxin treatment increased endogenous S202/T205 tau phosphorylation in CA3 neurons. In picrotoxin-treated mice, cfos expression was associated with increased tau phosphorylation specifically in CA3 and CA1 neurons. Together, these findings identify activity-dependent, endogenous tau phosphorylation as a selective response to hyperexcitation in excitatory hippocampal neurons downstream of PKA activation. The data further link tau phosphorylation to altered GluA2 regulation, suggesting a potential molecular connection between neuronal hyperactivity, tau phosphorylation, and synaptic dysfunction relevant to AD. Significance Statement Neuronal hyperactivity induced endogenous tau phosphorylation at S202/T205 selectively in excitatory hippocampal pyramidal neurons, the same neurons vulnerable to tau aggregation in Alzheimer’s disease (AD). Tau phosphorylation at this site was sufficient to induce downregulation of surface GluA2, implicating phosphorylation of endogenous tau in regulating the response to neuronal hyperactivity. These findings suggest that neuronal hyperactivation modulates tau phosphorylation, potentially linking neuronal hyperexcitation, selective neuronal vulnerability, and synaptic dysfunction in AD.

Key findings

• Extending these findings to mice, chronic low-dose picrotoxin treatment increased endogenous S202/T205 tau phosphorylation in CA3 neurons.
• In picrotoxin-treated mice, cfos expression was associated with increased tau phosphorylation specifically in CA3 and CA1 neurons.
• Together, these findings identify activity-dependent, endogenous tau phosphorylation as a selective response to hyperexcitation in excitatory hippocampal neurons downstream of PKA activation.
• These findings suggest that neuronal hyperactivation modulates tau phosphorylation, potentially linking neuronal hyperexcitation, selective neuronal vulnerability, and synaptic dysfunction in AD.

Study details

• Evidence strengthLow

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• DOI: 10.64898/2026.10.26.762028
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@article{sun2026-f4157059,
  author  = {Sun, M. N. and Vaughey, K. and Liu, B. and Guo, H. and Huganir, R. and Morris, M.},
  title   = {{Neuronal Hyperactivity Induces Tau Phosphorylation Selectively in Excitatory Pyramidal Neurons Which Contributes to GluA2 Regulation}},
  journal = {bioRxiv},
  year    = {2026},
  doi     = {10.64898/2026.10.26.762028},
  url     = {https://doi.org/10.64898/2026.10.26.762028}
}

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