Reduced cooperativity of voltage-gated sodium channels in the hippocampal interneurons of an aged mouse model of Alzheimer’s disease

Abstract

Beta amyloid (Aβ) associated with Alzheimer’s disease (AD) leads to abnormal behavior in inhibitory neurons, resulting in hyperactive neuronal networks, epileptiform behavior, disrupted gamma rhythms, and aberrant synaptic plasticity. Previously, we used a dual modeling-experimental approach to explain several observations, including failure to reliably produce action potentials (APs), smaller AP amplitudes, higher resting membrane potential, and higher membrane depolarization in response to a range of stimuli in hippocampal inhibitory neurons from 12–16 month old female APPswe/PSEN1DeltaE9 (APdE9) AD mice as compared to age-matched non-transgenic (NTG) mice. Our experimental results also showed that AP initiation in interneurons from APdE9 mice are significantly different from that of NTG mice. APs in interneurons from NTG mice are characterized by abrupt onset and an upstroke that is much steeper and occurs with larger variability as compared to cells from APdE9 mice. The phase plot (the rate of change of membrane potential versus the instantaneous membrane potential) of APs produced by interneurons from APdE9 mice shows a biphasic behavior whereas that from NTG mice shows a monophasic behavior. Here we show that using the classic Hodgkin-Huxley (HH) formalism for the gating of voltage-gated sodium channels (VGSCs) in a single-compartment neuron, we cannot reproduce these features and a model that takes into account a cooperative activation of VGSCs is needed. We also argue that considering a realistic multi-compartment neuron where the kinetics of VGSC is modeled by HH formalism as done in the past, wouldn’t explain our observations when APs from both NTG and APdE9 mice are considered simultaneously. We further show that VGSCs in interneurons from APdE9 mice exhibit significantly lower cooperativity in their activation as compared to those form NTG mice.

The effect of sodium channels on neurological/neuronal disorders: A systematic review

“…It has been reported that these defects in sporadic AD patients do widely not spread (Vossel et al, 2013;Vossel et al, 2016;Lam et al, 2017). Furthermore, the increase in Aβ oligomers is related to a reduction in long-term potentiation (Oddo et al, 2003;Walsh et al, 2002;Townsend et al, 2006;Mirzaei et al, 2018), elevated synaptic depression, and cognitive disturbance (Perez & Ullah, 2018;Shekarian et al, 2020).…”

“…Moreover, other studies have shown that the single-compartment neuronal model utilizing the classic Hodgkin-Huxley (HH) formalism of VGSCs failed to reproduce all characteristics of APs generated by interneurons from both nontransgenic (NTG) and APdE9 mice (McCormick et al, 2007;Yu et al, 2008). For this purpose, by comparing the results obtained from the models of activation of VGSCs with experimental findings, it was found that Aβ compared with the cells of NTG mice decreased the cooperativity in the activation of VGSCs in interneurons of APdE9 mice (Perez & Ullah, 2018).…”

Collective Dynamics of Ion Channels on Bilayer Lipid Membranes

“…For example, the oligomerization of VDAC is important in mitochondrial signaling and apoptosis, , and the clustering of IP3 receptors has been found to regulate Ca 2+ puff during calcium signaling . Especially in the case of neurons, clustering of ion channels can significantly affect action potential dynamics. ,, Clustering could facilitate interaction among neighboring ion channels, thus enhancing or inhibiting the gating of its surrounding channels. ,− It has been mentioned by various authors that the capability of ion channel clusters to represent enhanced gating dynamics should be viewed as a collective phenomenon. − …”