Sensory input drives rapid homeostatic scaling of the axon initial segment in mouse barrel cortex

Abstract

The axon initial segment (AIS) is an important axonal microdomain for action potential initiation and implicated in the regulation of neuronal excitability during activity-dependent cortical plasticity. While structural AIS plasticity has been suggested to fine-tune neuronal activity when network states change, whether it acts as a homeostatic regulatory mechanism in behaviorally relevant contexts remains poorly understood. Using an in vivo model of the mouse whisker-to-barrel pathway in combination with immunofluorescence, confocal analysis and patch-clamp electrophysiological recordings, we observed bidirectional AIS plasticity. Furthermore, we find that structural and functional AIS remodeling occurs in distinct temporal domains: long-term sensory deprivation elicits an AIS length increase, accompanied with an increase in neuronal excitability, while sensory enrichment results in a rapid AIS shortening, accompanied by a decrease in action potential generation. Our findings highlight a central role of the AIS in the homeostatic regulation of neuronal inputoutput relations.

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

“…In contrast, changes in AIS length have a much clearer corollary. Experimental and theoretical results are in close agreement that, all else being equal, a shorter AIS leads to decreased excitability (Evans et al, 2015;Goethals and Brette, 2020;Grubb and Burrone, 2010;Gulledge and Bravo, 2016;Höfflin et al, 2017;Jamann et al, 2020;Kuba et al, 2010;Pan-Vazquez et al, 2020;Sohn et al, 2019;Wefelmeyer et al, 2015;Werginz et al, 2020). Our data showing brief sensory deprivation-induced AIS shortening and decreased excitability in OB DA neurons are entirely consistent with this coherent picture.…”

Brief sensory deprivation triggers cell type-specific structural and functional plasticity in olfactory bulb neurons

“…In contrast, changes in AIS length have a much clearer corollary. Experimental and theoretical results are in close agreement that, all else being equal, a shorter AIS leads to decreased excitability (Evans et al, 2015;Goethals and Brette, 2019;Grubb and Burrone, 2010;Gulledge and Bravo, 2016;Höfflin et al, 2017;Jamann et al, 2020;Kuba et al, 2010;Pan-Vazquez et al, 2020;Sohn et al, 2019;Wefelmeyer et al, 2015). Our data showing brief sensory deprivationinduced AIS shortening and decreased excitability in OB DA neurons are entirely consistent with this coherent picture.…”

“…Importantly, while changes in both AIS position and length have been described in cultured neurons (Chand et al, 2015;Dumitrescu et al, 2016;Evans et al, 2013Evans et al, , 2015Grubb and Burrone, 2010), plasticity of AIS position without any accompanying length change has yet to be described in intact networks. Indeed, all in vivo activity-dependent AIS plasticity described to date seems to express itself as length changes ( Fig.8 here; (Höfflin et al, 2017;Jamann et al, 2020;Kuba et al, 2010;Pan-Vazquez et al, 2020)). Failure to describe in vivo AIS position changes could be due to a physical impediment to moving this macromolecular structure, which is tightly linked to extracellular matrix proteins (Brückner et al, 2006), when the overall 3D circuit structure is in place.…”

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

Structural and Functional Maturation of Rat Primary Motor Cortex Layer V Neurons

“…Our observations suggest that postnatal AIS elongation largely contributes to the maturation of several output properties in growing M1LV neurons. In sensory cortices, phases of postnatal AIS remodeling are associated with phasic adaptation of intrinsic neuronal excitability [ 15 , 17 , 18 , 37 ]. In contrast, the AIS of M1LV neurons underwent continuous elongation without phasic remodeling of intrinsic excitability.…”