VARIABILITY IN AXON INITIAL SEGMENT GEOMETRY OF HUMAN TEMPORAL LOBE NEURONS

The axon initial segment (AIS) is the most proximal portion of the axon where action potentials are generated, serving as a critical determinant of neuronal excitability. Axons originating from dendrites, termed axon-carrying dendrites (AcDs), enable specialized modes of signal processing but were previously considered rare in humans. Studies in rodents have shown that AIS geometry and scaling with soma size influence neuronal output, yet comparable human data are limited.
To address this, we applied a robust immunohistochemical staining protocol to neurosurgically resected temporal lobe tissue from tumor and epilepsy patients. Confocal microscopy and three-dimensional reconstruction allowed quantitative analysis of AIS geometry across all six neocortical layers. Over 11,000 neurons and nearly 7,000 AIS from 10 patients were examined. Layer-specific differences in neuronal density, soma size, and AIS geometry were observed, with AcDs more frequent in deeper cortical layers (up to 25%). Comparative analyses across epilepsy cohorts revealed potential AIS alterations in chronic pharmaco-resistant cases. Also, rare AIS morphologies, such as forked AIS structures, were identified.
This large-scale dataset provides novel insights into human AIS diversity, layer-specific distribution, and AcD prevalence. Future studies will combine the use of additional immunohistochemical markers, electrophysiology and computational modeling to link AIS geometry to neuronal excitability and cortical information processing, advancing understanding of human temporal lobe circuitry in health and disease.