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

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.

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

Science Advances ◽

10.1126/sciadv.abb6642 ◽

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.

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NuMA1 promotes axon initial segment assembly through inhibition of endocytosis

The Journal of Cell Biology ◽

10.1083/jcb.201907048 ◽

2019 ◽

pp. jcb.201907048 ◽

Cited By ~ 3

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.

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

Journal of Cell Science ◽

10.1242/jcs.256180 ◽

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.

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GABAergic Synapses at the Axon Initial Segment of Basolateral Amygdala Projection Neurons Modulate Fear Extinction

Neuropsychopharmacology ◽

10.1038/npp.2016.205 ◽

2016 ◽

Vol 42 (2) ◽

pp. 473-484 ◽

Cited By ~ 14

Author(s):

Rinki Saha ◽

Stephanie Knapp ◽

Darpan Chakraborty ◽

Omer Horovitz ◽

Anne Albrecht ◽

...

Keyword(s):

Initial Segment ◽

Basolateral Amygdala ◽

Fear Extinction ◽

Axon Initial Segment ◽

Projection Neurons ◽

Gabaergic Synapses

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Cytoskeletal organization of axons in vertebrates and invertebrates

The Journal of Cell Biology ◽

10.1083/jcb.201912081 ◽

2020 ◽

Vol 219 (7) ◽

Cited By ~ 2

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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