Tau-dependent Kv4.2 depletion and dendritic hyperexcitability in a mouse model of Alzheimer's disease

J Neurosci. 2015 Apr 15;35(15):6221-30. doi: 10.1523/JNEUROSCI.2552-14.2015.


Neuronal hyperexcitability occurs early in the pathogenesis of Alzheimer's disease (AD) and contributes to network dysfunction in AD patients. In other disorders with neuronal hyperexcitability, dysfunction in the dendrites often contributes, but dendritic excitability has not been directly examined in AD models. We used dendritic patch-clamp recordings to measure dendritic excitability in the CA1 region of the hippocampus. We found that dendrites, more so than somata, of hippocampal neurons were hyperexcitable in mice overexpressing Aβ. This dendritic hyperexcitability was associated with depletion of Kv4.2, a dendritic potassium channel important for regulating dendritic excitability and synaptic plasticity. The antiepileptic drug, levetiracetam, blocked Kv4.2 depletion. Tau was required, as crossing with tau knock-out mice also prevented both Kv4.2 depletion and dendritic hyperexcitability. Dendritic hyperexcitability induced by Kv4.2 deficiency exacerbated behavioral deficits and increased epileptiform activity in hAPP mice. We conclude that increased dendritic excitability, associated with changes in dendritic ion channels including Kv4.2, may contribute to neuronal dysfunction in early stages AD.

Keywords: Alzheimer; Kv4.2; amyloid-beta; dendrites; excitability; tau.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / genetics
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / genetics
  • Alzheimer Disease / pathology*
  • Amyloid beta-Peptides / pharmacology
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Brain Waves / drug effects
  • Brain Waves / genetics
  • CA1 Region, Hippocampal / drug effects
  • CA1 Region, Hippocampal / pathology*
  • Dendrites / physiology*
  • Female
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Humans
  • In Vitro Techniques
  • Levetiracetam
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation / genetics
  • Neurons / drug effects
  • Neurons / pathology*
  • Nootropic Agents / pharmacology
  • Piracetam / analogs & derivatives
  • Piracetam / pharmacology
  • Shal Potassium Channels / deficiency*
  • Shal Potassium Channels / genetics
  • tau Proteins / deficiency*
  • tau Proteins / genetics


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Nootropic Agents
  • Shal Potassium Channels
  • tau Proteins
  • Levetiracetam
  • Piracetam