Structural and Functional Refinement of the Axon Initial Segment in Avian Cochlear Nucleus during Development

Abstract

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 mm long with few voltage-gated sodium channels regardless of tonotopic region. However, after hatching, the AIS matured and displayed an ;20-mm-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.

Brief Sensory Deprivation Triggers Cell Type-Specific Structural and Functional Plasticity in Olfactory Bulb Neurons

“…In vitro , elevated activity can cause the AIS of excitatory neurons to relocate distally or to decrease in length, structural changes that are usually associated with decreased functional excitability ( Grubb and Burrone, 2010 ; Evans et al, 2013 , 2015 ; Muir and Kittler, 2014 ; Chand et al, 2015 ; Horschitz et al, 2015 ; Wefelmeyer et al, 2015 ; Lezmy et al, 2017 ; Sohn et al, 2019 ). In vivo , activity-dependent structural AIS plasticity has been observed in excitatory neurons, usually induced by manipulations that are long in duration and/or involve damage to peripheral sensory organs ( Kuba et al, 2010 ; Gutzmann et al, 2014 ; Akter et al, 2020 ; Pan-Vazquez et al, 2020 ; but see Jamann et al, 2021 ). But is AIS plasticity a prerogative of excitatory neurons, or is it also included in the plasticity toolkit of inhibitory cells?…”

Formin Activity and mDia1 Contribute to Maintain Axon Initial Segment Composition and Structure

“…Thus, formin inhibition-mediated actin modifications seem to play only a minor role on AIS length, due to cisternal organelle alterations, previously shown to play a role in AIS length plasticity [27]. Moreover, actin rings do not change during AIS developmental reorganization and shortening [68]. In this sense, mDia1 modulates actin-independent mechanisms, such as the spine density recovery, after Aβ peptide treatment, by an actin-binding-deficient K994A mDia1 mutant [67].…”

Pathophysiological Roles of Abnormal Axon Initial Segments in Neurodevelopmental Disorders

“…Physiological recordings also showed that these cells become more excitable [65]. The same research team recently reported that the regulation of cytoskeletal reorganization and sodium channel enrichment in the AIS differs depending on tonotopy (the spatial arrangement of sound frequency processing in the brain), but acts synergistically in the auditory nucleus [66]. These results indicate that neurons adapt to presynaptic activity and maintain neural circuit homeostasis by altering the properties of the AIS.…”