Pathogenic Tau Impairs Axon Initial Segment Plasticity and Excitability Homeostasis

Sohn, Peter; Huang, Cindy; Yan, Rui; Fan, Li; Tracy, Tara E.; Camargo, Carolina M.; Montgomery, Kelly M.; Arhar, Taylor; Mok, Sue-Ann; Freilich, Rebecca; Baik, Justin; He, Manni; Gong, Shiaoching; Roberson, Erik D.; Karch, Celeste M.; Gestwicki, Jason E.; Xu, Ke; Kosik, Kenneth S.; Gan, Li

doi:10.1016/j.neuron.2019.08.008

Cited by 108 publications

(136 citation statements)

References 72 publications

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“…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.…”

Section: Can We Use Structure To Predict Function In Vivo? Ais Propersupporting

confidence: 87%

“…How is AIS plasticity driven by changes in neuronal activity? 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)).…”

Section: Introductionmentioning

confidence: 99%

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

Galliano

Hahn

Browne

et al. 2020

Preprint

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Can alterations in experience trigger different plastic modifications in neuronal structure and function, and if so, how do they integrate at the cellular level? To address this question, we interrogated circuitry in the mouse olfactory bulb responsible for the earliest steps in odour processing. We induced experience-dependent plasticity in mice by blocking one nostril for a day, a minimally-invasive manipulation which leaves the sensory organ undamaged and is akin to the natural transient blockage suffered during common mild rhinal infections. We found that such brief sensory deprivation produced structural and functional plasticity in one highly specialised bulbar cell type: axon-bearing dopaminergic neurons in the glomerular layer. After 24h naris occlusion, the axon initial segment (AIS) in bulbar dopaminergic neurons became significantly shorter, a structural modification that was also associated with a decrease in intrinsic excitability. These effects were specific to the AIS-positive dopaminergic subpopulation, because no experience-dependent alterations in intrinsic excitability were observed in AIS-negative dopaminergic cells. Moreover, 24h naris occlusion produced no structural changes at the AIS of bulbar excitatory neuronsmitral/tufted and external tufted cells -nor did it alter their intrinsic excitability. By targeting excitability in one specialised dopaminergic subpopulation, experience-dependent plasticity in early olfactory networks might act to fine-tune sensory processing in the face of continually fluctuating inputs.

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Section: Can We Use Structure To Predict Function In Vivo? Ais Propersupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

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

Galliano

Hahn

Browne

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…However, denervation of NMJs in aged animals indicates a functional decline. Notably, the AIS pathology might additionally explain the observed functional behavioral and motoric alterations despite a lack of degeneration in young animals: alterations of the AIS due to, for example, mutations in Tau were shown to affect neuronal excitability (Sohn et al, 2019). Similarly, the altered morphology of the AIS in Tmem106b KO mice might cause functional deficits.…”

Section: Discussionmentioning

confidence: 99%

The FTLD Risk Factor TMEM106B Regulates the Transport of Lysosomes at the Axon Initial Segment of Motoneurons

et al. 2020

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“…Intrinsic to achieving this goal is the need to advance our understanding of the regulatory programs that determine alternative splicing and posttranslational modifications, both of which we know virtually nothing about in ankyrins and spectrins, together with how they may modulate cell‐specific and local functions. Although remarkable progress has been made in uncovering the roles of ankyrins and spectrins as principal actors in the AIS, we do not fully understand how they integrate into the developing model of AIS plasticity and its relevance to disease (Sohn et al, ). Technical advances, such as AIS‐targeted proteomics (Hamdan et al, ), should enable us to gain deeper insights into the organization and function of AIS.…”

Section: Perspectivesmentioning

confidence: 99%

Cargo hold and delivery: Ankyrins, spectrins, and their functional patterning of neurons

Lorenzo

2020

Cytoskeleton

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The highly polarized, typically very long, and nonmitotic nature of neurons present them with unique challenges in the maintenance of their homeostasis. This architectural complexity serves a rich and tightly controlled set of functions that enables their fast communication with neighboring cells and endows them with exquisite plasticity. The submembrane neuronal cytoskeleton occupies a pivotal position in orchestrating the structural patterning that determines local and long‐range subcellular specialization, membrane dynamics, and a wide range of signaling events. At its center is the partnership between ankyrins and spectrins, which self‐assemble with both remarkable long‐range regularity and micro‐ and nanoscale specificity to precisely position and stabilize cell adhesion molecules, membrane transporters, ion channels, and other cytoskeletal proteins. To accomplish these generally conserved, but often functionally divergent and spatially diverse, roles these partners use a combinatorial program of a couple of dozens interacting family members, whose code is not fully unraveled. In a departure from their scaffolding roles, ankyrins and spectrins also enable the delivery of material to the plasma membrane by facilitating intracellular transport. Thus, it is unsurprising that deficits in ankyrins and spectrins underlie several neurodevelopmental, neurodegenerative, and psychiatric disorders. Here, I summarize key aspects of the biology of spectrins and ankyrins in the mammalian neuron and provide a snapshot of the latest advances in decoding their roles in the nervous system.

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Pathogenic Tau Impairs Axon Initial Segment Plasticity and Excitability Homeostasis

Abstract: Highlights d The FTD-causing V337M tau mutation impairs axon initial segment (AIS) plasticity d The V337M tau mutation impairs activity homeostasis d The V337M tau mutation leads to accumulation of EB3 in the AIS d EB3 is critical for regulating AIS plasticity and activity homeostasis

Cited by 108 publications

References 72 publications

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

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

The FTLD Risk Factor TMEM106B Regulates the Transport of Lysosomes at the Axon Initial Segment of Motoneurons

Cargo hold and delivery: Ankyrins, spectrins, and their functional patterning of neurons

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