Modelling the contributions to hyperexcitability in a mouse model of Alzheimer's disease.

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 in-creased 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 biophysi-cally 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 degen-eration 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 (I AHP down-regulated; I Nap , I Na and I CaT 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: Simulations of synaptically driven responses in PCs with AD-related dendritic degener- ation. Dendritic degeneration alone alters PC responses to layer-specific input but additional pathomechanistic scenarios are required to explain neuronal hyperexcitability in AD. 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 proper- ties can account for hyperexcitability in AD. Possible scenario 3: Burst hyperactivity of the surrounding network can explain hyper- excitability of PCs during AD. Abstract figure legend Three scenarios of extrinsic and intrinsic mechanisms can explain hyperexcitability of APP/PS1 model pyramidal cells Using a computational model, we find that changes in the extrinsic network and intrinsic biophysical neuronal properties rather than dendritic degeneration alone explain the altered firing behaviour (i.e., increased firing rates and transition to bursting) observed in Alzheimer's disease (AD). This article is protected by copyright. All rights reserved.