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

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Neurophysiology Aims and scope

Signaling pathways of neurons depend on such factors as the type and “strength” of the synapse, cable properties, distribution of ion channels, and biophysical parameters involved. Aggregation of amyloidbeta (Aβ) in Alzheimer’s disease (AD) dramatically affects the functioning of neurons (hippocampal CA1 pyramidal neurons in particular) in multiple ways, which results in loss of memory and cognitive intelligence. To date, the respective available cell models have been focused on individual channel mechanisms involved, without considering the combined effect of those. Due to this, exact information on the respective dysfunction caused in the cell was limited. Therefore, we adopted a methodology analogous to that in studies of neural networks, which takes into account different combinations of the channel mechanisms, to address changes in the number of action potentials (APs) generated (AP counts) in the model. We have taken into consideration decreases in the conductance of A-type potassium channels (KA), delayed rectifier potassium channels (KDR), and sodium channels (Na) in succession to simulate the effect of agglomeration of Aβ. At the same time, we tried to include individual calcium channels, namely L-type (CaL), N-type (CaN), T-type (CaT), and calcium-sensitive potassium channels (Cagk) in unique combinations to identify the behavior and significance of each channel for different input-output relations at locations on the soma and proximal dendrites of the cell. Each of these steps were taken at four distinct AD-influenced stages (30, 60, 90, and 100%). In this study, we found that decreases in the conductance of KA channels induces hyperexcitability, while decreases in the conductance of KDR and Na channels induce hypoexcitability of the neuron. In comparison with KDR, Na channels are highly responsive to CaL, CaN, CaT, and Cagk, and the respective effects are rather significant. In this model, the effects of compensation or rectification on Aβ accumulation were brought about by three methods: first, by altering the conductance of Na channels, second, by reducing the amplitude of input current, and finally, by an equitable combination of both. We found that a higher amount of compensation is required to restore the normal AP counts of the cell under the influence of CaL, as compared with the effects of CaN channels (when each of these are individually included). The model anticipates the potential therapeutic treatments in terms of pharmacological modifications of the channel kinetics.

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  1. Biomedical Engineering Department, Government Engineering College, Sector-28, Gandhinagar, Gujarat, India

    J. Garg, A. Lakhani & V. Dave

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Correspondence to J. Garg.

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Garg, J., Lakhani, A. & Dave, V. Effects of the Involvement of Calcium Channels on Neuronal Hyperexcitability Related to Alzheimer’s Disease: A Computational Model. Neurophysiology 52, 334–347 (2020). https://doi.org/10.1007/s11062-021-09890-9

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  • DOI: https://doi.org/10.1007/s11062-021-09890-9

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