Electrical gears: How axonal domains and myelin shape spike output

Abstract

Electrical signalling is fundamental to nervous system function and the underlying process that gives rise to thoughts, memories, sensations and actions. The most critical electrical signals are called action potentials, that are generated at the axon initial segment (AIS) and propagate along myelinated axons by saltatory conduction. In this thesis, we studied how axonal microdomains including the AIS, its inhibitory synapses as well as the internodal myelination, control the spiking output of neurons in sensory systems. In Chapter 2, we investigated AIS plasticity in the developing and adult mouse barrel cortex, revealing bidirectional, homeostatic structural changes dependent on sensory input. Using sensory deprivation and enrichment paradigms, we showed that AIS length correlates with intrinsic neuronal excitability and can be rapidly shortened within hours, emphasizing its role in maintaining network balance in behaving animals in vivo. Chapter 3 explored the molecular mechanisms of rapid AIS plasticity. Using a novel protocol with brief NMDA application and live-cell reporter tools, we induced and tracked AIS shortening in individual neurons. We found that NMDA triggered calcineurin-dependent endocytosis of Ankyrin G and sodium channels from the distal AIS, reducing intrinsic excitability. This study uncovered key pathways regulating AIS structural dynamics. In Chapter 4, we examined chandelier cell (ChC) connectivity in the primary visual cortex, demonstrating their non-reciprocal input to layer 2/3 neurons and primary drive from layer 5 (L5) and long-range projections. Visual training altered ChC bouton numbers and induced AIS shortening, linking structural plasticity to network connectivity and behaviour. Chapter 5 focused on myelination’s role in signal propagation along the L5–POm pathway. We found that selective grey matter myelin loss led to L5 nodal domain remodelling, causing action potential failures and spike timing jitter. These disruptions impaired the precise temporal integration of whisker-evoked signals in POm, underscoring myelin’s critical role in ensuring reliable signal transmission and timing precision.