Analysis of Age-Dependent Alterations in Excitability Properties of CA1 Pyramidal Neurons in an APPPS1 Model of Alzheimer’s Disease

Abstract

Age-dependent accumulation of amyloid-β, provoking increasing brain amyloidopathy, triggers abnormal patterns of neuron activity and circuit synchronization in Alzheimer’s disease (AD) as observed in human AD patients and AD mouse models. Recent studies on AD mouse models, mimicking this age-dependent amyloidopathy, identified alterations in CA1 neuron excitability. However, these models generally also overexpress mutated amyloid precursor protein (APP) and presenilin 1 (PS1) and there is a lack of a clear correlation of neuronal excitability alterations with progressive amyloidopathy. The active development of computational models of AD points out the need of collecting such experimental data to build a reliable disease model exhibiting AD-like disease progression. We therefore used the feature extraction tool of the Human Brain Project (HBP) Brain Simulation Platform to systematically analyze the excitability profile of CA1 pyramidal neuron in the APPPS1 mouse model. We identified specific features of neuron excitability that best correlate either with over-expression of mutated APP and PS1 or increasing Aβ amyloidopathy. Notably, we report strong alterations in membrane time constant and action potential width and weak alterations in firing behavior. Also, using a CA1 pyramidal neuron model, we evidence amyloidopathy-dependent alterations in Ih. Finally, cluster analysis of these recordings showed that we could reliably assign a trace to its correct group, opening the door to a more refined, less variable analysis of AD-affected neurons. This inter-disciplinary analysis, bringing together experimentalists and modelers, helps to further unravel the neuronal mechanisms most affected by AD and to build a biologically plausible computational model of the AD brain.

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

“…The hyperexcitability in AD cells has also been previously linked to ion channel modifications (Chen, 2005; Beck and Yaari, 2008; Brown et al ., 2011; Zhang et al ., 2014; Kerrigan et al ., 2014; Liu et al ., 2015; Wang et al ., 2015b,a, 2016; Musial et al ., 2018; Ghatak et al ., 2019; Villa et al ., 2020; Vitale et al ., 2021; Müller et al ., 2021). Therefore, we explored which combination of these previously reported ion channel changes led to an increase of excitability in the APP/PS1 morphologies.…”

“…Our simulations showed that, although ion channel modifications alone led to an increased firing of especially bursts ( Supplementary Figure S4C , Middle panel ), they did not reproduce quantitatively the output mode transition from single spiking to predominantly burst firing as reported in figure 1B of (Šišková et al ., 2014). We tested also changes of other ion channels that have been linked to hyperexcitability including potassium, L-type calcium and hyperpolarisation-activated, cyclic nucleotide-gated HCN channels (Beck and Yaari, 2008; Musial et al ., 2018; Vitale et al ., 2021) but our simulations did not show a significant contribution to the increase in burst activity (see Methods).…”

“…The basis of cellular hyperactivity in AD remains poorly understood. Several studies have investigated this phenomenon, either by using neuronal cultures and organoids (Ghatak et al ., 2019), by in vitro (Šišková et al ., 2014) and in vivo (Palop et al ., 2007; Busche et al ., 2008, 2012; Šišková et al ., 2014; Verret et al ., 2012; Busche and Konnerth, 2016; Palop and Mucke, 2016; Sosulina et al ., 2021) approaches, as well as computational modelling (Šišková et al ., 2014; van Elburg and van Ooyen, 2010; Vitale et al ., 2021). Some of these studies suggested that the increased firing and bursting activity of the AD cells could be explained by neurite degeneration (Šišková et al ., 2014; Ghatak et al ., 2019) given that reduced dendritic length and complexity promotes the intrinsic excitability and integration of synaptic inputs (van Elburg and van Ooyen, 2010).…”

“…For the effect of ion channel changes alone in Supplementary Figure S4C we scaled the aforementioned ion channel conductances to additional values (0.05 for I AHP and 3 for I Nap , I Na and I CaT ) in order to investigate a possible maximum burst firing increase (with minimal change in single spike firing) under pathological ion channel conditions. Furthermore, we tested alterations of other ion channels that are mentioned in literature in relation to AD including potassium and hyperpolarisation-activated, cyclic nucleotide-gated HCN channels, which have been proposed to be involved in hyperexcitability (Beck and Yaari, 2008; Musial et al ., 2018; Vitale et al ., 2021). However, our simulations did not show a significant contribution to the increase in burst activity of APP/PS1 CA1 PC morphologies.…”

“…Likewise, increased excitability has also been documented in a mouse model of AD, where it was attributed to changes in the dendritic tree and alterations in the expression and function of A-type K + channels (Hall et al ., 2015). There has been contradictory evidence showing the role of the hyperpolarisation-activated H channel with studies indicating both a decrease or an increase of its density (Musial et al ., 2018; Vitale et al ., 2021). Further experimental findings have revealed the influence of the small and large calcium-activated K + channels in AD model mice (Beck and Yaari, 2008; Zhang et al ., 2014; Wang et al ., 2015a,b).…”