title: Dendritic structural degeneration is functionally linked to cellular hyperexcitability in a mouse model of Alzheimer's disease.
abstract: Dendritic structure critically determines the electrical properties of neurons and, thereby, defines the fundamental process of input-to-output conversion. The diversity of dendritic architectures enables neurons to fulfill their specialized circuit functions during cognitive processes. It is known that this dendritic integrity is impaired in patients with Alzheimer's disease and in relevant mouse models. It is unknown, however, whether this structural degeneration translates into aberrant neuronal function. Here we use in vivo whole-cell patch-clamp recordings, high-resolution STED imaging, and computational modeling of CA1 pyramidal neurons in a mouse model of Alzheimer's disease to show that structural degeneration and neuronal hyperexcitability are crucially linked. Our results demonstrate that a structure-dependent amplification of synaptic input to action potential output conversion might constitute a novel cellular pathomechanism underlying network dysfunction with potential relevance for other neurodegenerative diseases with abnormal changes of dendritic morphology.
authors.affiliation: Neuronal Networks Group, Deutsches Zentrum für Neurodegenerative Erkrankungen, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Šišková
authors.affiliation: Neuronal Networks Group, Deutsches Zentrum für Neurodegenerative Erkrankungen, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Justus
authors.affiliation: Neuronal Networks Group, Deutsches Zentrum für Neurodegenerative Erkrankungen, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kaneko
authors.affiliation: Neuronal Networks Group, Deutsches Zentrum für Neurodegenerative Erkrankungen, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
authors.forename: Detlef
authors.initials: D
authors.lastname: Friedrichs
authors.affiliation: Neuronal Networks Group, Deutsches Zentrum für Neurodegenerative Erkrankungen, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
authors.forename: Niklas
authors.initials: N
authors.lastname: Henneberg
authors.affiliation: Neuronal Networks Group, Deutsches Zentrum für Neurodegenerative Erkrankungen, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Beutel
authors.affiliation: Section of Translational Epilepsy Research, Department of Neuropathology, University of Bonn Medical Center, Sigmund-Freud-Straße 25, 53125 Bonn, Germany.
authors.forename: Julika
authors.initials: J
authors.lastname: Pitsch
authors.affiliation: Section of Translational Epilepsy Research, Department of Neuropathology, University of Bonn Medical Center, Sigmund-Freud-Straße 25, 53125 Bonn, Germany; Department of Epileptology, University of Bonn Medical Center, Sigmund-Freud-Straße 25, 53125 Bonn, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schoch
authors.affiliation: Section of Translational Epilepsy Research, Department of Neuropathology, University of Bonn Medical Center, Sigmund-Freud-Straße 25, 53125 Bonn, Germany.
authors.forename: Albert
authors.initials: A
authors.lastname: Becker
authors.affiliation: Neurobiology, Evotec AG, Essener Bogen 7, 22419 Hamburg, Germany.
authors.forename: Heinz
authors.initials: H
authors.lastname: von der Kammer
authors.affiliation: Neuronal Networks Group, Deutsches Zentrum für Neurodegenerative Erkrankungen, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany; Department of Epileptology, University of Bonn Medical Center, Sigmund-Freud-Straße 25, 53125 Bonn, Germany. Electronic address: stefan.remy@dzne.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Remy
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D003198:Computer Simulation; D003712:Dendrites / Q000473:pathology*; D004195:Disease Models, Animal; D004558:Electric Stimulation; D005260:Female; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D066298:In Vitro Techniques; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008959:Models, Neurological; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000209:etiology* / Q000473:pathology*; D009474:Neurons / Q000473:pathology*; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; D053764:Presenilin-1; C013411:biocytin; D008239:Lysine