Simulating Action Potential Initiation and Propagation in Physically Detailed Damaged and Healthy Neurons

Abstract

This thesis presents single-compartment and multi-compartmental neuron models. We simulated injury-induced pathological spiking patterns, as well as heterogeneous ion channel distributions in the axon initial segment (AIS) and their impact on backpropagation. In neurons, voltage-gated sodium and potassium ion channels (𝖭𝖺ᵥs and 𝖪ᵥs, respectively) regulate ionic currents across the cell membrane in the production of action potentials (APs). As such, channel dynamics feature throughout this thesis. The starting point was the Coupled left-shift (𝐶𝐿𝑆) model of cellular damage, wherein the gating properties of 𝖭𝖺ᵥs are thrown "out of tune" by injury (left-shift, 𝐿𝑆), such that the subpopulation of affected channels (𝐴𝐶) no longer responds correctly to homeostatic membrane potentials. We simulated a single-compartment neuron with 𝐶𝐿𝑆-type damage and systematically mapped out its excitability regimes in the 𝐿𝑆-𝐴𝐶 plane. Next, we added temperature sensitivity to the 𝖭𝖺ᵥ and 𝖪ᵥ gating kinetics and maximal conductances, the Nernst potentials, and the Na⁺/K⁺ pump. We compared the neuron's ability to cope with 𝐶𝐿𝑆 damage when temperature effects were added one by one, to the case where all effects act together as they would in nature. The former "knock-in/knock-out" simulations revealed the importance of (i.e. model sensitivity to) each temperature-driven change in the ionic currents that govern excitability. Our multicompartmental pyramidal cell models indicate that the pattern of ion channels in the AIS affects feedback sent to synapses in the soma and dendrites. Inserting a set of hypothetical 𝖭𝖺ᵥ distributions into the AIS, we found that the impact of 𝖭𝖺ᵥ subtypes on the neuron's backpropagation threshold depends on the mode of stimulation (orthodromic or antidromic). Both modes are used by experimentalists, and our results should inform comparative studies as well as the design of neural prosthetics, as the AIS is a logical target for multielectrode arrays used in brain-computer interfaces. Coupled left-shift in the AIS produced axonal hypersensitivity, decoupled the somatic backpropagation threshold from the AP threshold, and modified backpropagation in a manner resembling polarity reversal of the AIS sodium channel pattern. Below the ectopic threshold, 𝐶𝐿𝑆 may interfere with homeostatic intracellular signalling and learning via the putative role of spike-timing-dependent plasticity in the dendrites.