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Free keywords:
degeneracy
dendritic constancy
hippocampus
morphological modelling
multi-causal pathogenesis
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.
