Axon Initial Segment plasticity: unravelling the mechanisms that control neuronal excitability

ongoing

Neurons have the remarkable ability to continuously integrate and propagate information while maintaining their activity state within physiological range. The axon initial segment (AIS) is the keystone of neuronal excitability and pivotal for the maintenance of network homeostasis. The molecular organization of the AIS dictates the generation of action potentials, and thereby shapes the principal output of neurons. Although the AIS has long been considered as a static and passive structure, recent work from my lab and others demonstrated that network activity induces robust plasticity of the AIS, causing long-lasting changes in excitability. However, how AIS plasticity is regulated to maintain network homeostasis remains elusive. In this proposal, I aim to resolve, at the molecular level, how the AIS adapts in response to acute and chronic changes in neuronal activity and how maladaptation may lead to disease. To this end, I developed genome editing tools to label and manipulate endogenous AIS components, enabling live and super-resolution imaging of AIS organization. In combination with proteomics, optogenetics and electrophysiology, this project will address the following key objectives: 1. Resolve the nanoscale distribution and dynamics of AIS components 2. Unravel the mechanisms controlling acute and chronic re-distribution of ion channels during AIS plasticity and their consequences for excitability 3. Address the implication of maladaptive AIS plasticity in the pathology of Angelman Syndrome This project bridges the cell biology of the neuron to its physiology, provides new insights into how AIS plasticity orchestrates network activity and identifies how maladaptation contributes to disease.