TY  - INPR
A1  - Mittag, Martin
A1  - Mediavilla Santos, Laura
A1  - Remy, Stefan
A1  - Cuntz, Hermann
A1  - Jedlička, Peter
T1  - Modelling the contributions to hyperexcitability in a mouse model of Alzheimer’s disease
T2  - bioRxiv
N2  - Neuronal hyperexcitability is a feature 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 excitability in reconstructed CA1 pyramidal neurons of 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 excitability decreasing effects of synaptic loss. We find an interesting balance of excitability regulation with 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 that three additional pathomechanistic scenarios can account for the experimentally observed increase in firing and bursting of CA1 pyramidal neurons in APP/PS1 mice. Scenario 1: increased excitatory burst input; scenario 2: enhanced E/I ratio and scenario 3: alteration of intrinsic ion channels (IAHP down-regulated; INap, INa and ICaT up-regulated) in addition to enhanced E/I ratio. 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 and degeneracy according to which multiple different disruptions are separately sufficient but no single disruption is necessary for neuronal hyperexcitability.
Y1  - 2022
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/73078
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-730787
IS  - 2022.06.29.494500
ER  -