Integrative dynamics of action potential in Axon Initial Segment (AIS) of neurons: A novel computational model : A thesis submitted in partial fulfilment of the requirements for the Degree of Doctor of Philosophy at Lincoln University

Abstract

The Axon Initial Segment (AIS) plays a critical role in neuronal excitability and action potential initiation. Computational modelling of the AIS can provide valuable insights into the biophysical mechanisms underlying these processes and their relevance to various AIS-related disorders. The Hodgkin-Huxley model laid the foundation for understanding action potential initiation, utilising empirical differential equations to describe sodium and potassium ion conductance and their gating functions. However, the specific role of the scaffold protein Ankrin-G (AnkG) in regulating ion channel function and ion currents in the AIS remains poorly understood. This thesis investigates the impact of AnkG concentration on sodium (Nav) and potassium (Kv) channel gating and ion current properties using electrophysiology, molecular biology, and computational modelling approaches. AnkG acts as a molecular bridge between the Nav and Kv channels and the cytoskeleton, ensuring proper channel localisation and density in the AIS. Disruptions to AnkG expression can lead to alterations in channel localisation and function, affecting neuronal excitability and firing properties. This thesis endeavors to unravel the mechanisms underlying AnkG's influence on Nav and Kv channel function and its subsequent impact on ion currents in the AIS. Understanding these interactions is crucial for comprehending the pathogenesis of AIS-related disorders and shed light on the complexities of action potential initiation and propagation in neurons.