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The axon initial segment (AIS) is involved in action potential initiation. Structural and biophysical characteristics of the AIS differ among cell types and/or brain regions, but the underlying mechanisms remain elusive. Using immunofluorescence and electrophysiological methods, combined with super-resolution imaging, we show in the developing nucleus magnocellularis of the chicken in both sexes that the AIS is refined in a tonotopic region-dependent manner. This process of AIS refinement differs among cells tuned to different frequencies. At hearing onset, the AIS was ∼50 µm long with few voltage-gated sodium channels regardless of tonotopic region. However, after hatching, the AIS matured and displayed an ∼20-µm-long structure with a significant enrichment of sodium channels responsible for an increase in sodium current and a decrease in spike threshold. Moreover, the shortening was more pronounced, while the accumulation of channels was not, in neurons tuned to higher frequency, creating tonotopic differences in the AIS. We conclude that AIS shortening is mediated by disassembly of the cytoskeleton at the distal end of the AIS, despite intact periodicity of the submembranous cytoskeleton across the AIS. Importantly, deprivation of afferent input diminished the shortening in neurons tuned to a higher frequency to a larger extent in posthatch animals, with little effect on the accumulation of sodium channels. Thus, cytoskeletal reorganization and sodium channel enrichment at the AIS are differentially regulated depending on tonotopic region, but work synergistically to optimize neuronal output in the auditory nucleus.SIGNIFICANCE STATEMENT The axon initial segment (AIS) plays fundamental roles in determining neuronal output. The AIS varies structurally and molecularly across tonotopic regions in avian cochlear nucleus. However, the mechanism underlying these variations remains unclear. The AIS is immature around hearing onset, but becomes shorter and accumulates more sodium channels during maturation, with a pronounced shortening and a moderate channel accumulation at higher tonotopic regions. Afferent input adjusts sodium conductance at the AIS by augmenting AIS shortening (via disassembly of cytoskeletons at its distal end) specifically at higher-frequency regions. However, this had little effect on channel accumulation. Thus, cytoskeletal structure and sodium channel accumulation at the AIS are regulated differentially but work synergistically to optimize the neuronal output. Copyright © 2020 the authors.


Nargis Akter, Ryota Fukaya, Ryota Adachi, Hiroshi Kawabe, Hiroshi Kuba. Structural and Functional Refinement of the Axon Initial Segment in Avian Cochlear Nucleus during Development. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2020 Aug 26;40(35):6709-6721

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PMID: 32719016

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