scholarly journals NuMA1 promotes axon initial segment assembly through inhibition of endocytosis

2019 ◽  
pp. jcb.201907048 ◽  
Author(s):  
Tomohiro Torii ◽  
Yuki Ogawa ◽  
Cheng-Hsin Liu ◽  
Tammy Szu-Yu Ho ◽  
Hamdan Hamdan ◽  
...  
Keyword(s):  
Transient Expression ◽  
Action Potentials ◽  
Initial Segment ◽  
Axon Initial Segment ◽  
Neonatal Mouse ◽  
Scaffolding Protein ◽  
Differential Proteomics ◽  
Mitotic Apparatus ◽  
Axon Initial Segments ◽  
Protein 4.1B

Axon initial segments (AISs) initiate action potentials and regulate the trafficking of vesicles between somatodendritic and axonal compartments. However, the mechanisms controlling AIS assembly remain poorly defined. We performed differential proteomics and found nuclear mitotic apparatus protein 1 (NuMA1) is downregulated in AIS-deficient neonatal mouse brains and neurons. NuMA1 is transiently located at the AIS during development where it interacts with the scaffolding protein 4.1B and the dynein regulator lissencephaly 1 (Lis1). Silencing NuMA1 or protein 4.1B by shRNA disrupts AIS assembly, but not maintenance. Silencing Lis1 or overexpressing NuMA1 during AIS assembly increased the density of AIS proteins, including ankyrinG and neurofascin-186 (NF186). NuMA1 inhibits the endocytosis of AIS NF186 by impeding Lis1’s interaction with doublecortin, a potent facilitator of NF186 endocytosis. Our results indicate the transient expression and AIS localization of NuMA1 stabilizes the developing AIS by inhibiting endocytosis and removal of AIS proteins.

scholarly journals Tailoring of the axon initial segment shapes the conversion of synaptic inputs into spiking output in OFF-α T retinal ganglion cells

2020 ◽  
Vol 6 (37) ◽  
pp. eabb6642
Author(s):  
Paul Werginz ◽  
Vineeth Raghuram ◽  
Shelley I. Fried
Keyword(s):  
Retinal Ganglion Cells ◽  
Initial Segment ◽  
Ganglion Cells ◽  
Axon Initial Segment ◽  
Retinal Ganglion ◽  
Light Responses ◽  
Synaptic Inputs ◽  
Dorsal Cells ◽  
Axon Initial Segments ◽  
Dorsal Retina

Recently, mouse OFF-α transient (OFF-α T) retinal ganglion cells (RGCs) were shown to display a gradient of light responses as a function of position along the dorsal-ventral axis; response differences were correlated to differences in the level of excitatory presynaptic input. Here, we show that postsynaptic differences between cells also make a strong contribution to response differences. Cells in the dorsal retina had longer axon initial segments (AISs)—the greater number of Nav1.6 channels in longer AISs directly mediates higher rates of spiking and helps avoid depolarization block that terminates spiking in ventral cells with shorter AISs. The pre- and postsynaptic specializations that shape the output of OFF-α T RGCs interact in different ways: In dorsal cells, strong inputs and the long AISs are both necessary to generate their strong, sustained spiking outputs, while in ventral cells, weak inputs or the short AISs are both sufficient to limit the spiking signal.

scholarly journals Contribution of the axon initial segment to action potentials recorded extracellularly

2018 ◽  
Author(s):  
Maria Teleńczuk ◽  
Romain Brette ◽  
Alain Destexhe ◽  
Bartosz Teleńczuk
Keyword(s):  
Action Potential ◽  
Electric Fields ◽  
Action Potentials ◽  
Initial Segment ◽  
Initiation Site ◽  
Axon Initial Segment ◽  
Neuron Activity ◽  
Classical Models ◽  
The Brain

AbstractAction potentials (APs) are electric phenomena that are recorded both intracellularly and extracellularly. APs are usually initiated in the short segment of the axon called the axon initial segment (AIS). It was recently proposed that at onset of an AP the soma and the AIS form a dipole. We study the extracellular signature (the extracellular action potential, EAP) generated by such a dipole. First, we demonstrate the formation of the dipole and its extracellular signature in detailed morphological models of a reconstructed pyramidal neuron. Then, we study the EAP waveform and its spatial dependence in models with axonal AP initiation and contrast it with the EAP obtained in models with somatic AP initiation. We show that in the models with axonal AP initiation the dipole forms between somatodendritic compartments and the AIS, and not between soma and dendrites as in the classical models. Soma-dendrites dipole is present only in models with somatic AP initiation. Our study has consequences for interpreting extracellular recordings of single-neuron activity and determining electrophysiological neuron types, but also for better understanding the origins of the high-frequency macroscopic electric fields recorded in the brain.New & NoteworthyWe studied the consequences of the action potential (AP) initiation site on the extracellular signatures of APs. We show that: (1) at the time of AP initiation the action initial segment (AIS) forms a dipole with the soma, (2) the width but not (3) amplitude of the extracellular AP generated by this dipole increases with the soma-AIS distance. This may help to monitor dynamic changes in the AIS position in experimental in vivo recordings.

scholarly journals Nanoscale architecture of the axon initial segment reveals an organized and robust scaffold

2015 ◽  
Author(s):  
Christophe Leterrier ◽  
Jean Potier ◽  
Ghislaine Caillol ◽  
Claire Debarnot ◽  
Fanny Rueda Boroni ◽  
...  
Keyword(s):  
Action Potentials ◽  
Initial Segment ◽  
Axon Initial Segment ◽  
Molecular Architecture ◽  
Physiological Functions ◽  
Structural Stabilization ◽  
Ankyrin G ◽  
Stochastic Optical Reconstruction Microscopy ◽  
Optical Reconstruction ◽  
Actin Rings

The Axon Initial Segment [AIS], located within the first 30 μm of the axon, has two essential roles in generating action potentials and maintaining axonal identity. AIS assembly depends on a βIV-spectrin / ankyrin G scaffold, but its macromolecular arrangement is not well understood. Here we quantitatively determined the AIS nanoscale architecture using STochastic Optical Reconstruction Microscopy [STORM]. First we directly demonstrate that the 190-nm periodicity of the AIS submembrane lattice results from longitudinal, head-to-head βIV-spectrin molecules connecting actin rings. Using multicolor 3D-STORM, we resolve the nanoscale organization of ankyrin G: its aminoterminus associates with the submembrane lattice, whereas the carboxyterminus radially extends (~32 nm on average) toward the cytosol. This AIS nano-architecture is highly resistant to cytoskeletal perturbations, advocating its role in structural stabilization. Our findings provide a comprehensive view of the AIS molecular architecture, and will help understanding the crucial physiological functions of this compartment.

scholarly journals Endogenously expressed Ranbp2 (Nup358) is not at the axon initial segment

2021 ◽  
pp. jcs.256180
Author(s):  
Yuki Ogawa ◽  
Matthew N. Rasband
Keyword(s):  
Nuclear Pore Complex ◽  
Nuclear Membrane ◽  
Initial Segment ◽  
Axon Initial Segment ◽  
Nuclear Pore ◽  
Cultured Neurons ◽  
Epitope Tag ◽  
Antibody Binding Site ◽  
Axon Initial Segments ◽  
Primary Cultured Neurons

Ranbp2 (also known as Nup358) is a member of the nucleoporin family that comprises the nuclear pore complex. Ranbp2 localizes at the nuclear membrane and was recently reported at the axon initial segment (AIS). However, we show the anti-Ranbp2 antibody used in previous studies is not specific for Ranbp2. We mapped the antibody binding site to the amino acid sequence KPLQG that is present in both Ranbp2 and Neurofascin, a well-known AIS protein. After silencing Neurofascin expression in neurons, the AIS was not stained by the antibody. Surprisingly, an exogenously expressed N-terminal fragment of Ranbp2 localizes at the AIS. We show this fragment interacts with stable microtubules. Finally, using CRISPR-Cas9 in primary cultured neurons, we inserted an HA-epitope tag at N-terminal, C-terminal, or internal sites of the endogenously expressed Ranbp2. No matter the location of the HA-epitope, endogenous Ranbp2 was found at the nuclear membrane but not the AIS. These results show that endogenously expressed Ranbp2 is not found at axon initial segments.

scholarly journals Theoretical relation between axon initial segment geometry and excitability

2019 ◽  
Author(s):  
Sarah Goethals ◽  
Romain Brette
Keyword(s):  
Theoretical Analysis ◽  
Action Potentials ◽  
Simple Formula ◽  
Initial Segment ◽  
Axon Initial Segment ◽  
Confounding Factors ◽  
Theoretical Relation ◽  
Modest Increase ◽  
The Many ◽  
The Impact

AbstractIn most vertebrate neurons, action potentials are triggered at the distal end of the axon initial segment (AIS). Both position and length of the AIS vary across and within neuron types, with activity, development and pathology. What is the impact of AIS geometry on excitability? Direct empirical assessment has proven difficult because of the many potential confounding factors. Here we carried a principled theoretical analysis to answer this question. We provide a simple formula relating AIS geometry and sodium conductance density to the somatic voltage threshold. A distal shift of the AIS normally produces a (modest) increase in excitability, but we explain how this pattern can reverse if a hyperpolarizing current is present at the AIS, due to resistive coupling with the soma. This work provides a theoretical tool to assess the significance of structural AIS plasticity for electrical function.

scholarly journals Pathological consequences of chronic olfactory inflammation on neurite morphology of olfactory bulb projection neurons

2021 ◽  
Author(s):  
Brandon Joseph LaFever ◽  
Yuka Imamura Kawasawa ◽  
Ayako Ito ◽  
Fumiaki Imamura
Keyword(s):  
Chronic Rhinosinusitis ◽  
Intranasal Administration ◽  
Initial Segment ◽  
Recovery Period ◽  
Axon Initial Segment ◽  
Projection Neurons ◽  
Inflammatory Cytokine Production ◽  
Response To Stress ◽  
Axon Initial Segments ◽  
Integrated Circuitry

Abstract Background : Chronic olfactory inflammation (COI) in conditions such as chronic rhinosinusitis significantly impairs the functional and anatomical components of the olfactory system. COI induced by intranasal administration of lipopolysaccharide (LPS) results in atrophy, gliosis, and pro-inflammatory cytokine production in the OB. Although chronic rhinosinusitis patients have smaller olfactory bulbs (OBs), the consequences of olfactory inflammation on OB neurons are largely unknown. Methods : In this study, we investigated the neurological consequence of COI on OB projection neurons, mitral cells (MCs) and tufted cells (TCs). To induce COI, we performed unilateral intranasal administration of LPS to mice for 4 and 10 weeks. Effects of COI on the OB were examined using RNA-sequencing approaches and immunohistochemical analyses. Results : We found that repeated LPS administration upregulated immune-related biological pathways in the OB after 4 weeks. We also determined that the length of TC lateral dendrites in the OB significantly decreased after 10 weeks of COI. The axon initial segment of TCs decreased in number and in length after 10 weeks of COI. The lateral dendrites and axon initial segments of MCs, however, were largely unaffected. In addition, dendritic arborization and axon initial segment reconstruction both took place following a 10-week recovery period. Conclusion : Our findings suggests that olfactory inflammation specifically affects TCs and their integrated circuitry, whereas MCs are potentially protected from this condition. This data demonstrates unique characteristics of the OBs ability to undergo neuroplastic changes in response to stress.

scholarly journals Characterization of the axon initial segment (AIS) of motor neurons and identification of a para-AIS and a juxtapara-AIS, organized by protein 4.1B

BMC Biology ◽  
2011 ◽  
Vol 9 (1) ◽  
pp. 66 ◽  
Author(s):  
Amandine Duflocq ◽  
Fabrice Chareyre ◽  
Marco Giovannini ◽  
François Couraud ◽  
Marc Davenne
Keyword(s):  
Motor Neurons ◽  
Initial Segment ◽  
Axon Initial Segment ◽  
Protein 4.1B

scholarly journals Cytoskeletal organization of axons in vertebrates and invertebrates

2020 ◽  
Vol 219 (7) ◽  
Author(s):  
Andreas Prokop
Keyword(s):  
Initial Segment ◽  
Growth Cones ◽  
Axon Initial Segment ◽  
Electron Microscopic ◽  
Cytoskeletal Organization ◽  
Ultrastructural Studies ◽  
Microscopic Studies ◽  
Different Dimensions ◽  
Plastic Changes ◽  
Axon Initial Segments

The maintenance of axons for the lifetime of an organism requires an axonal cytoskeleton that is robust but also flexible to adapt to mechanical challenges and to support plastic changes of axon morphology. Furthermore, cytoskeletal organization has to adapt to axons of dramatically different dimensions, and to their compartment-specific requirements in the axon initial segment, in the axon shaft, at synapses or in growth cones. To understand how the cytoskeleton caters to these different demands, this review summarizes five decades of electron microscopic studies. It focuses on the organization of microtubules and neurofilaments in axon shafts in both vertebrate and invertebrate neurons, as well as the axon initial segments of vertebrate motor- and interneurons. Findings from these ultrastructural studies are being interpreted here on the basis of our contemporary molecular understanding. They strongly suggest that axon architecture in animals as diverse as arthropods and vertebrates is dependent on loosely cross-linked bundles of microtubules running all along axons, with only minor roles played by neurofilaments.

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