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@ARTICLE{Mittag:256459,
      author       = {Mittag, Martin and Mediavilla, Laura and Remy, Stefan and
                      Cuntz, Hermann and Jedlicka, Peter},
      title        = {{M}odelling the contributions to hyperexcitability in a
                      mouse model of {A}lzheimer's disease.},
      journal      = {The journal of physiology},
      volume       = {601},
      number       = {15},
      issn         = {0022-3751},
      address      = {Hoboken, NJ},
      publisher    = {Wiley-Blackwell},
      reportid     = {DZNE-2023-00321},
      pages        = {3403-3437},
      year         = {2023},
      note         = {CC BY},
      abstract     = {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.},
      keywords     = {Mice / Animals / Alzheimer Disease / Hippocampus:
                      physiology / Neurons: physiology / Pyramidal Cells:
                      physiology / Ion Channels: metabolism / Disease Models,
                      Animal / Ion Channels (NLM Chemicals) / degeneracy (Other) /
                      dendritic constancy (Other) / hippocampus (Other) /
                      morphological modelling (Other) / multi-causal pathogenesis
                      (Other)},
      cin          = {AG Remy},
      ddc          = {610},
      cid          = {I:(DE-2719)1013006},
      pnm          = {351 - Brain Function (POF4-351)},
      pid          = {G:(DE-HGF)POF4-351},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36734280},
      doi          = {10.1113/JP283401},
      url          = {https://pub.dzne.de/record/256459},
}