Computational study of hippocampal-septal theta rhythm changes due to β-amyloid-altered ionic channels.

Stephen D Ginsberg,Xin Zou,Kongfatt Wong-Lin,Liam Maguire,Damien Coyle

doi:10.1371/journal.pone.0021579

Abstract

Electroencephagraphy (EEG) of many dementia patients has been characterized by an increase in low frequency field potential oscillations. One of the characteristics of early stage Alzheimer’s disease (AD) is an increase in theta band power (4–7 Hz). However, the mechanism(s) underlying the changes in theta oscillations are still unclear. To address this issue, we investigate the theta band power changes associated with β-Amyloid (Aβ) peptide (one of the main markers of AD) using a computational model, and by mediating the toxicity of hippocampal pyramidal neurons. We use an established biophysical hippocampal CA1-medial septum network model to evaluate four ionic channels in pyramidal neurons, which were demonstrated to be affected by Aβ. They are the L-type Ca2+ channel, delayed rectifying K+ channel, A-type fast-inactivating K+ channel and large-conductance Ca2+-activated K+ channel. Our simulation results demonstrate that only the Aβ inhibited A-type fast-inactivating K+ channel can induce an increase in hippocampo-septal theta band power, while the other channels do not affect theta rhythm. We further deduce that this increased theta band power is due to enhanced synchrony of the pyramidal neurons. Our research may elucidate potential biomarkers and therapeutics for AD. Further investigation will be helpful for better understanding of AD-induced theta rhythm abnormalities and associated cognitive deficits.

Highlights

Alzheimer’s disease (AD) is a neurodegenerative disease associated with memory deficits and cognitive decline, which may be induced by anatomical and physiological changes in the brain
As a first step in our study, we focus on the changes in these four ionic channels, i.e., Ltype Ca2+ channel (ICa); A-type fast-inactivating K+ channel (IA), delayed rectifying K+ channel (IK) and large-conductance Ca2+activated K+ channel (ICT), and evaluate any corresponding change in hippocampal theta band power
The patterns of oscillation changes in different frequency bands have been used to discriminate the AD-induced dementia from the other dementias [41]

Summary

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disease associated with memory deficits and cognitive decline, which may be induced by anatomical and physiological changes in the brain. AD is characterized by two neuropathological structures: neurofibrillary tangles and senile plaques. The neurofibrillary tangles are the residue of neuronal death, which may be caused by the microtubule-binding protein, tau, becoming hyperphosphorylated. The senile plaques are mainly composed of Ab. Ab acts as a neurotoxin causing neuronal dysfunction and apoptosis [1]. As Ab precedes tau protein in AD progress [2], we will focus on Ab in this work

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