ICAR3R - Interdisciplinary Centre for 3Rs in Animal Research, Justus Liebig University Giessen, Giessen, Germany.
School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK.
J Physiol. 2023 Aug;601(15):3403-3437. doi: 10.1113/JP283401. Epub 2023 Feb 25.
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 (I down-regulated; I , I and I 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.
神经元过度兴奋是阿尔茨海默病（AD）的一种病理特征。有三种主要机制被提出解释这种现象：（i）树突退化导致输入电阻增加，（ii）离子通道变化导致固有兴奋性增强，以及（iii）突触变化导致兴奋-抑制（E/I）失衡。然而，这些机制的相对贡献尚不完全清楚。因此，我们对来自野生型和 APP/PS1 小鼠的 CA1 锥体神经元进行了生物物理上逼真的多室模型构建，以研究 AD 的一种成熟的动物模型。我们表明，对于突触激活，树突退化的兴奋性促进作用被由于突触丢失而导致的兴奋性降低所抵消。我们发现 APP/PS1 细胞的基底树突中存在一种有趣的兴奋调节和增强退化之间的平衡，这可能导致通过顶树突的兴奋性增加，而通过基底 Schaffer 侧支通路的兴奋性降低。此外，我们的模拟揭示了三种能够解释 APP/PS1 小鼠 CA1 锥体神经元中观察到的放电和爆发增加的病理机制情景：情景 1：增强的 E/I 比值；情景 2：除增强的 E/I 比值之外，还改变了内在离子通道（I 下调；I ，I 和 I 上调）；情景 3：增加兴奋性爆发输入。我们的工作支持这样的假设，即病理性网络和离子通道变化是 AD 中神经元过度兴奋的主要原因。总的来说，我们的结果与多因果性的概念一致，根据该概念，多种不同的破坏分别是足够的，但对于神经元过度兴奋，没有单一特定的破坏是必要的。要点：这项工作提出了与阿尔茨海默病（AD）相关的树突退化的锥体细胞（PC）的突触驱动反应的模拟。单独的树突退化改变了 PC 对层特异性输入的反应，但需要额外的病理机制情景来解释 AD 中的神经元过度兴奋，如下所示。可能的情景 1：AD 相关的兴奋性输入增加加上抑制性输入减少（E/I 失衡）可导致 PC 过度兴奋。可能的情景 2：E/I 平衡的变化与离子通道特性的改变可以解释 AD 中的过度兴奋。可能的情景 3：周围网络的爆发活动可以解释 AD 期间 PC 的过度兴奋。
