title: Tau-dependent Kv4.2 depletion and dendritic hyperexcitability in a mouse model of Alzheimer's disease.
abstract: 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.
authors: Center for Neurodegeneration and Experimental Therapeutics, Departments of Neurology, Neurobiology, and.
authors: Alicia M
authors: AM
authors: Hall
authors: Molecular Neurophysiology and Biophysics Section, Eunice Kennedy Shriver National Institute for Child Health and Development, National Institutes of Health, Bethesda, Maryland 20892.
authors: Benjamin T
authors: http://orcid.org/0000-0001-6834-8263
authors: BT
authors: Throesch
authors: Neurobiology, and.
authors: Susan C
authors: http://orcid.org/0000-0003-2483-3544
authors: SC
authors: Buckingham
authors: Neurobiology, and.
authors: Sean J
authors: SJ
authors: Markwardt
authors: Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294, and.
authors: Yin
authors: Y
authors: Peng
authors: Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294, and.
authors: Qin
authors: Q
authors: Wang
authors: Molecular Neurophysiology and Biophysics Section, Eunice Kennedy Shriver National Institute for Child Health and Development, National Institutes of Health, Bethesda, Maryland 20892 hoffmand@mail.nih.gov eroberson@uab.edu.
authors: Dax A
authors: DA
authors: Hoffman
authors: Center for Neurodegeneration and Experimental Therapeutics, Departments of Neurology, Neurobiology, and hoffmand@mail.nih.gov eroberson@uab.edu.
authors: Erik D
authors: http://orcid.org/0000-0002-1810-9763
authors: ED
authors: Roberson
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D058256:Brain Waves / Q000187:drug effects / Q000235:genetics; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000473:pathology*; D003712:Dendrites / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D000077287:Levetiracetam; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D018697:Nootropic Agents / Q000494:pharmacology; D010889:Piracetam / Q000031:analogs & derivatives / Q000494:pharmacology; D051672:Shal Potassium Channels / Q000172:deficiency* / Q000235:genetics; D016875:tau Proteins / Q000172:deficiency* / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018697:Nootropic Agents; D051672:Shal Potassium Channels; D016875:tau Proteins; D000077287:Levetiracetam; D010889:Piracetam
keywords: Alzheimer; Kv4.2; amyloid-beta; dendrites; excitability; tau