Effects of the Involvement of Calcium Channels on Neuronal Hyperexcitability Related to Alzheimer’s Disease: A Computational Model

Garg, J.; Lakhani, A.; Dave, Vijay

doi:10.1007/s11062-021-09890-9

Cited by 2 publications

(8 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Ion channel alterations represent another potential mechanism of AD-associated neuronal hyperexcitability. Therefore, in the third scenario, in addition to the enhanced E/I ratio, we have included changes in ion channel currents observed in data from literature: downregulation of I AHP ; upregulation of I Nap , I Na and I CaT (see Methods for more details) (Yaari et al ., 2007; Beck and Yaari, 2008; Zhang et al ., 2014; Wang et al ., 2015a,b; Liu et al ., 2015; Wang et al ., 2016; Ghatak et al ., 2019; Niday and Bean, 2021; Garg et al ., 2021). The input pattern and example time profile for Scenario 3 were the same as in Scenario 2 and can be seen in Figure 4B (coefficient of variation of input per cell, WT: cv = 0.41, APP/PS1: cv = 0.41 and modified APP/PS1 in Scenario 3: cv = 0.17).…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, we explored which combination of these previously reported ion channel changes led to an increase of excitability in the APP/PS1 morphologies. In line with experimental findings, we found several ion channel changes that increased the overall spike rate and burst firing: down-regulation of I AHP (Beck and Yaari, 2008; Zhang et al ., 2014; Wang et al ., 2015a; Niday and Bean, 2021), up-regulation of I Na and persistent I Nap (Williams and Stuart, 1999; Yue et al ., 2005; Beck and Yaari, 2008; Liu et al ., 2015; Wang et al ., 2016; Ghatak et al ., 2019) and up-regulation of T-type calcium current I CaT (Yaari et al ., 2007; Beck and Yaari, 2008; Cain and Snutch, 2013; Medlock et al ., 2018; Garg et al ., 2021). 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).…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, the voltage-dependent sodium channel INa in the axon (Liu et al ., 2015; Wang et al ., 2016; Ghatak et al ., 2019) was upscaled 1.3-fold and the persistent sodium channel INap in the soma (Williams and Stuart, 1999; Yue et al ., 2005; Beck and Yaari, 2008) was upscaled 2-fold in Figure 4E of Scenario 3 for extrinsic ( E/I balance) and intrinsic (ion channel) modifications. At the same time the medium afterhyperpolarisation calcium-activated potassium channel I AHP in the soma and apical dendrites was downscaled 0.85-fold (Beck and Yaari, 2008; Zhang et al ., 2014; Wang et al ., 2015b,a; Niday and Bean, 2021) in Figure 4E , while the T-type calcium channel in dendrites (Yaari et al ., 2007; Beck and Yaari, 2008; Cain and Snutch, 2013; Medlock et al ., 2018; Garg et al ., 2021) was upscaled 2-fold. 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.…”

Section: Methodsmentioning

confidence: 99%

“…For AD-related pathologies the L-type Ca 2+ channel (Anekonda et al ., 2011; Berridge, 2014), the A-type K + channel (Chen, 2005) and Na + channels (Wang et al ., 2016; Ghatak et al ., 2019; Müller et al ., 2021) have been shown to be involved in burst rate amplification. Modelling studies (Medlock et al ., 2018; Garg et al ., 2021) confirm the role of Ca 2+ channels for enhanced burst firing. Evidently, the modification of intrinsic excitability due to alterations in ion channel expression is well documented in AD.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Mittag

Mediavilla

Remy

et al. 2022

Preprint

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Mittag

Mediavilla

Remy

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…For AD‐related pathologies the L‐type Ca 2+ channel (Anekonda et al., 2011; Berridge, 2014), the A‐type K + channel (Chen, 2005) and Na + channels (Ghatak et al., 2019; Müller et al., 2021; Wang et al., 2016) have been shown to be involved in burst rate amplification. Modelling studies (Garg et al., 2021; Medlock et al., 2018) confirm the role of Ca 2+ channels for enhanced burst firing. Evidently, the modification of intrinsic excitability due to alterations in ion channel expression is well documented in AD.…”

Section: Introductionmentioning

confidence: 90%

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

Mittag

Mediavilla

Remy

et al. 2023

The Journal of Physiology

View full text Add to dashboard Cite

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.

show abstract

Effects of the Involvement of Calcium Channels on Neuronal Hyperexcitability Related to Alzheimer’s Disease: A Computational Model

Cited by 2 publications

References 47 publications

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

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

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

Contact Info

Product

Resources

About