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The Journal of Physiology - 2023 - Mittag.pdf 4,58MB
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1000 Titel
  • Modelling the contributions to hyperexcitability in a mouse model of Alzheimer's disease
1000 Autor/in
  1. Mittag, Martin |
  2. Mediavilla Santos, Laura |
  3. Remy, Stefan |
  4. Cuntz, Hermann |
  5. Jedlicka, Peter |
1000 Erscheinungsjahr 2023
1000 LeibnizOpen
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2023-02-03
1000 Erschienen in
1000 Quellenangabe
  • 601(15):3403-3437
1000 FRL-Sammlung
1000 Copyrightjahr
  • 2023
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.1101/2022.06.29.494500 |
1000 Ergänzendes Material
  • https://physoc.onlinelibrary.wiley.com/doi/10.1113/JP283401#support-information-section |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • Neuronal hyperexcitability is a pathological characteristic of Alzheimer's disease (AD). Three main mechanisms have been proposed to explain it: (i) dendritic degeneration leading to increased input resistance, (ii) ion channel changes leading to enhanced intrinsic excitability, and (iii) synaptic changes leading to excitation-inhibition (E/I) imbalance. However, the relative contribution of these mechanisms is not fully understood. Therefore, we performed biophysically realistic multi-compartmental modelling of neuronal excitability in reconstructed CA1 pyramidal neurons from wild-type and APP/PS1 mice, a well-established animal model of AD. We show that, for synaptic activation, the excitability-promoting effects of dendritic degeneration are cancelled out by decreased excitation due to synaptic loss. We find an interesting balance between excitability regulation and an enhanced degeneration in the basal dendrites of APP/PS1 cells, potentially leading to increased excitation by the apical but decreased excitation by the basal Schaffer collateral pathway. Furthermore, our simulations reveal three pathomechanistic scenarios that can account for the experimentally observed increase in firing and bursting of CA1 pyramidal neurons in APP/PS1 mice: scenario 1: enhanced E/I ratio; scenario 2: alteration of intrinsic ion channels (IAHP down-regulated; INap , INa and ICaT up-regulated) in addition to enhanced E/I ratio; and scenario 3: increased excitatory burst input. Our work supports the hypothesis that pathological network and ion channel changes are major contributors to neuronal hyperexcitability in AD. Overall, our results are in line with the concept of multi-causality according to which multiple different disruptions are separately sufficient but no single particular disruption is necessary for neuronal hyperexcitability. KEY POINTS: This work presents simulations of synaptically driven responses in pyramidal cells (PCs) with Alzheimer's disease (AD)-related dendritic degeneration. Dendritic degeneration alone alters PC responses to layer-specific input but additional pathomechanistic scenarios are required to explain neuronal hyperexcitability in AD as follows. Possible scenario 1: AD-related increased excitatory input together with decreased inhibitory input (E/I imbalance) can lead to hyperexcitability in PCs. Possible scenario 2: changes in E/I balance combined with altered ion channel properties can account for hyperexcitability in AD. Possible scenario 3: burst hyperactivity of the surrounding network can explain hyperexcitability of PCs during AD.
1000 Sacherschließung
lokal degeneracy
lokal dendritic constancy
lokal morphological modelling
lokal hippocampus
lokal multi-causal pathogenesis
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
  1. https://orcid.org/0000-0002-6429-2423|https://orcid.org/0000-0003-4174-4076|https://orcid.org/0000-0002-3386-1662|https://orcid.org/0000-0001-5445-0507|https://orcid.org/0000-0001-6571-5742
1000 (Academic) Editor
1000 Label
1000 Förderer
  1. Projekt DEAL |
1000 Fördernummer
  1. -
1000 Förderprogramm
  1. Open Access Funding
1000 Dateien
1000 Förderung
  1. 1000 joinedFunding-child
    1000 Förderer Projekt DEAL |
    1000 Förderprogramm Open Access Funding
    1000 Fördernummer -
1000 Objektart article
1000 Beschrieben durch
1000 @id frl:6461896.rdf
1000 Erstellt am 2023-09-12T11:22:41.823+0200
1000 Erstellt von 242
1000 beschreibt frl:6461896
1000 Bearbeitet von 317
1000 Zuletzt bearbeitet 2023-09-26T14:30:56.634+0200
1000 Objekt bearb. Tue Sep 26 14:30:38 CEST 2023
1000 Vgl. frl:6461896
1000 Oai Id
  1. oai:frl.publisso.de:frl:6461896 |
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