Feedback-Driven Assembly of the Axon Initial Segment

Fréal, Amélie; Rai, Dipti; Tas, Roderick P.; Pan, Xingxiu; Katrukha, Eugene A.; Willige, Dieudonnée van de; Stucchi, Riccardo; Aher, Amol; Yang, Chao; Altelaar, A.F. Maarten; Vocking, Karin; Post, Jan Andries; Harterink, Martin; Kapitein, Lukas C.; Akhmanova, Anna; Hoogenraad, Casper C.

doi:10.1016/j.neuron.2019.07.029

Cited by 64 publications

(80 citation statements)

References 80 publications

(154 reference statements)

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“…Corroborating data for a long-term plasticity mechanism has been provided by studies of the avian and mammalian auditory system, where at least one week of deprivation was required in order to elicit AIS elongation and changes in neuronal excitability (Kim et al, 2019;Kuba et al, 2010). Interestingly, our data suggests that elongation only occurs at the distal end of the AIS, which requires protein biosynthesis and axonal transport of the macromolecular complexes via the microtubule network towards the distal site, and subsequent protein assembly (Freal et al, 2019). This energetically "expensive" task is presumably time-consuming, particularly considering the vast downstream network of molecular binding partners localized in the AIS (Hamdan et al, 2020).…”

Section: Bidirectional Temporally Diverse Forms Of Ais Plasticitysupporting

confidence: 64%

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

Jamann

Dannehl

Wagener

et al. 2020

Preprint

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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.

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Section: Bidirectional Temporally Diverse Forms Of Ais Plasticitysupporting

confidence: 64%

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

Jamann

Dannehl

Wagener

et al. 2020

Preprint

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“…This idea is consistent with the observed shift of the unidirectional parallel microtubule organization in the distal parts of the axon first, followed by proximal reorganization. Finally, AnkG and Trim46 together may drive AIS assembly at the proximal axon, as previously described in dissociated rodent neurons (Freal et al 2019). It remains unknown if the observed intermediate step of distal AIS protein accumulation is unique to human neurons.…”

Section: Distal To Proximal Relocation Of Ais Proteins During Axon Dementioning

confidence: 60%

“…Although the precise relation between AIS formation and microtubule remodeling in early axon development is unclear, various studies have shown the cooperative interaction between AIS components and microtubule structures during axon development (Leterrier et al 2011;Freal et al 2016). Recently Fréal et al, described a feedback-based mechanism that drives AIS assembly, in which membrane, scaffolding, and microtubule(-associated) proteins, including AnkG and Trim46, cooperate to form a stable AIS-microtubule structure in the proximal axon (Freal et al 2019). It has been shown that AnkG can act as a scaffold to recruit Trim46-positive microtubules and subsequently direct AIS protein trafficking to the proximal axon (Freal et al 2019).…”

Section: Distal To Proximal Relocation Of Ais Proteins During Axon Dementioning

confidence: 99%

“…Recently Fréal et al, described a feedback-based mechanism that drives AIS assembly, in which membrane, scaffolding, and microtubule(-associated) proteins, including AnkG and Trim46, cooperate to form a stable AIS-microtubule structure in the proximal axon (Freal et al 2019). It has been shown that AnkG can act as a scaffold to recruit Trim46-positive microtubules and subsequently direct AIS protein trafficking to the proximal axon (Freal et al 2019). The possible function of AIS proteins in the distal axon remains elusive.…”

Section: Distal To Proximal Relocation Of Ais Proteins During Axon Dementioning

confidence: 99%

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Quantitative mapping of transcriptome and proteome dynamics during polarization of human iPSC-derived neurons

Lindhout

Kooistra

Portegies

et al. 2020

Preprint

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Early neuronal development is a well-coordinated process in which neuronal stem cells differentiate into polarized neurons. This process has been well studied in classical non-human model systems, but to what extent this is recapitulated in human neurons remains unclear. To study neuronal polarization in human neurons, we cultured human iPSC-derived neurons, characterized early developmental stages, measured electrophysiological responses, and systematically profiled transcriptomic and proteomic dynamics during these steps. We found extensive remodeling of the neuron transcriptome and proteome, with altered mRNA expression of ~1,100 genes and different expression profiles of ~1,500 proteins during neuronal differentiation and polarization. We also identified a distinct stage in axon development marked by an increase in microtubule remodeling and apparent relocation of the axon initial segment from the distal to proximal axon. Our comprehensive characterization and quantitative map of transcriptome and proteome dynamics provides a solid framework for studying polarization in human neurons.(FOM, #16NEPH05, CJW). AUTHOR CONTRIBUTIONSFWL, RK and SP designed the research, conducted experiments, and wrote the article together with LJH. RS conducted and analyzed the mass spectrometry experiments supervised by MA, LJH performed and interpreted the electrophysiology data supervised by CJW, RK and BLS provided and interpreted the RNA sequencing analysis. HDM edited the article. CCH designed the experimental plan, supervised the research and wrote the article.

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“…Image analysis was performed using the open source software Fiji (https://imagej.net/Fiji). Colocalization of Kcnk2 with Tph2 and Pet-1 was established using the plugin ComDet (https://github.com/ekatrukha/ComDet) 25 . Briefly, the plugin determines small ROIs each channel independently and determines if they colocalize spatially with up to 4 pixels of distance from each other.…”

Section: Rnascope Quantificationmentioning

confidence: 99%

Circadian photoperiod alters TREK-1 channel function and expression in dorsal raphe serotonergic neurons

Giannoni-Guzmán

Kamitakahara

Magalong

et al. 2020

Preprint

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AbstractSeasonal daylength has been linked to the development and prevalence of mood disorders, however, the neural mechanisms underlying this relationship remain unknown. Previous work in our laboratory has shown that developmental exposure to seasonal photoperiods has enduring effects on the activity of mouse dorsal raphe serotonergic neurons, their intrinsic electrical properties, as well as on depression and anxiety-related behaviors. Here we focus on the possible ionic mechanisms that underlie the observed photoperiodic programming of the electrophysiological properties of serotonin neurons, focusing on the twin-pore K+ channels TREK-1 and TASK-1 that set resting membrane potential and regulate excitability. Using multielectrode array recordings in ex vivo dorsal raphe slices, we examined the effects of pharmacological inhibition of these channels on the spike rates of serotonin neurons of mice from different photoperiods. Pharmacological inhibition of TREK-1 significantly increased spike frequency in Short and Equinox photoperiod cohorts, but did not further elevate the firing rate in slices from Long photoperiod mice, suggesting that TREK-1 function is reduced in Long photoperiods. In contrast, inhibition of TASK-1 resulted in increases in firing rates across all photoperiods, suggesting that it contributes to setting excitability, but is not regulated by photoperiod. To examine if photoperiod impacts transcriptional regulation of TREK-1, we quantified Kcnk2 mRNA levels specifically in dorsal raphe 5-HT neurons using triple-label RNAscope. We found that Long photoperiod significantly reduced levels of Kcnk2 in serotonin neurons co-expressing Tph2, and Pet-1, Photoperiodic effects on the function and expression of TREK-1 were blocked in melatonin 1 receptor knockout (MT-1KO) mice, consistent with previous findings that MT-1 signaling is necessary for photoperiodic programming of dorsal raphe 5-HT neurons. Taken together these results indicate that photoperiodic regulation of TREK-1 expression and function plays a key role in photoperiodic programming the excitability of dorsal raphe 5-HT neurons.

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Feedback-Driven Assembly of the Axon Initial Segment

Cited by 64 publications

References 80 publications

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

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

Quantitative mapping of transcriptome and proteome dynamics during polarization of human iPSC-derived neurons

Circadian photoperiod alters TREK-1 channel function and expression in dorsal raphe serotonergic neurons

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