Tropomyosin Tpm3.1 is required to maintain the structure and function of the axon initial segment

AbstractGABAergic interneurons are chiefly responsible for controlling the activity of local circuits in the cortex1,2. However, the rules that govern the wiring of interneurons are not well understood3. Chandelier cells (ChCs) are a type of GABAergic interneuron that control the output of hundreds of neighbouring pyramidal cells through axo-axonic synapses which target the axon initial segment (AIS)4. Despite their importance in modulating circuit activity, our knowledge of the development and function of axo-axonic synapses remains elusive. In this study, we investigated the role of activity in the formation and plasticity of ChC synapses. In vivo imaging of ChCs during development uncovered a narrow window (P12-P18) over which axons arborized and formed connections. We found that increases in the activity of either pyramidal cells or individual ChCs during this temporal window resulted in a reversible decrease in axo-axonic connections. Voltage imaging of GABAergic transmission at the AIS showed that axo-axonic synapses were depolarising during this period. Identical manipulations of network activity in older mice (P40-P46), when ChC synapses are inhibitory, resulted in an increase in axo-axonic synapses. We propose that the direction of ChC plasticity follows homeostatic rules that depend on the polarity of axo-axonic synapses.

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Tropomyosin Tpm3.1 is required to maintain the structure and function of the axon initial segment

10.1101/711614 ◽

2019 ◽

Cited By ~ 1

Author(s):

Amr Abouelezz ◽

Holly Stefen ◽

Mikael Segerstråle ◽

David Micinski ◽

Rimante Minkeviciene ◽

...

Keyword(s):

Actin Filaments ◽

Hippocampal Neurons ◽

Initial Segment ◽

Actin Polymerization ◽

Firing Frequency ◽

Axon Initial Segment ◽

Action Potential Initiation ◽

Sodium Ion Channels ◽

And Function ◽

Filament Network

ABSTRACTThe axon initial segment (AIS) is the site of action potential initiation and serves as a vesicular filter and diffusion barrier that help maintain neuronal polarity. Recent studies have revealed details about a specialized structural complex in the AIS. While an intact actin cytoskeleton is required for AIS formation, pharmacological disruption of actin polymerization compromises the AIS vesicle filter but does not affect overall AIS structure. In this study, we found that the tropomyosin isoform Tpm3.1 decorates a population of relatively stable actin filaments in the AIS. Inhibiting Tpm3.1 in cultured hippocampal neurons led to the loss of AIS structure, the AIS vesicle filter, the clustering of sodium ion channels, and reduced firing frequency. We propose that Tpm3.1-decorated actin filaments form a stable actin filament network under the AIS membrane which provides a scaffold for membrane organization and AIS proteins.

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A Perspective on the Role of Dynamic Alternative RNA Splicing in the Development, Specification, and Function of Axon Initial Segment

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2019.00295 ◽

2019 ◽

Vol 12 ◽

Cited By ~ 2

Author(s):

Takatoshi Iijima ◽

Takeshi Yoshimura

Keyword(s):

Rna Splicing ◽

Initial Segment ◽

Axon Initial Segment ◽

And Function

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Mitochondrial Structure and Polarity in Dendrites and the Axon Initial Segment are Regulated by Homeostatic Plasticity and Dysregulated in Fragile X Syndrome

10.21203/rs.3.rs-158378/v1 ◽

2021 ◽

Author(s):

Pernille Bülow ◽

Peter A Wenner ◽

Victor Faundez ◽

Gary J Bassell

Keyword(s):

Fragile X Syndrome ◽

Neurodevelopmental Disorders ◽

Neuronal Plasticity ◽

Cortical Neurons ◽

Initial Segment ◽

Fragile X ◽

Axon Initial Segment ◽

Homeostatic Plasticity ◽

Mitochondrial Morphology ◽

And Function

Abstract Mitochondrial dysfunction has long been overlooked in neurodevelopmental disorders, but recent studies have provided new links to genetic forms of autism, including Rett syndrome and Fragile X Syndrome (FXS). In parallel, recent studies have uncovered important basic functions of mitochondria to power protein synthesis, synaptic plasticity and neuronal maturation. The mitochondrion also responds to neuronal activity by altering its morphology and function, and this plasticity of the mitochondrion appear important for proper neuronal plasticity. Previous research has reported disease induced changes in mitochondrial morphology and function, but it remains unknown how such abnormalities affect the ability of mitochondria to express activity dependent plasticity. This study addresses this gap in knowledge using a mouse model of FXS. We previously reported abnormalities in one type of homeostatic plasticity, called homeostatic intrinsic plasticity, which is known to involve structural changes in the axon initial segment (AIS). Another form of homeostatic plasticity, called synaptic scaling, which involves postsynaptic changes in dendrites, is also impaired in FXS. It remains unknown if or how homeostatic plasticity affects mitochondria in axons and/or dendrites and whether impairments occur in neurodevelopmental disorders. Here, we test the hypothesis that mitochondria are structurally and functionally modified in a compartment specific manner during homeostatic plasticity in cortical neurons from wild type mice, and that this plasticity-induced regulation is altered in Fmr1 KO neurons, as a model of FXS. We uncovered dendritic specific regulation of mitochondrial surface area, whereas AIS mitochondria show changes in polarity; both responses are lost in Fmr1 KO. Taken together our results demonstrate impairments in mitochondrial plasticity in FXS, which has not previously been reported. These results suggest that mitochondrial dysregulation in FXS contributes to abnormal neuronal plasticity, with broader implications to other neurodevelopmental disorders and therapeutic strategies.

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Mitochondrial Structure and Polarity in Dendrites and the Axon Initial Segment Are Regulated by Homeostatic Plasticity and Dysregulated in Fragile X Syndrome

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.702020 ◽

2021 ◽

Vol 9 ◽

Author(s):

Pernille Bülow ◽

Peter A. Wenner ◽

Victor Faundez ◽

Gary J. Bassell

Keyword(s):

Fragile X Syndrome ◽

Neurodevelopmental Disorders ◽

Cortical Neurons ◽

Initial Segment ◽

Fragile X ◽

Axon Initial Segment ◽

Homeostatic Plasticity ◽

Mitochondrial Morphology ◽

Specific Regulation ◽

And Function

Mitochondrial dysfunction has long been overlooked in neurodevelopmental disorders, but recent studies have provided new links to genetic forms of autism, including Rett syndrome and fragile X syndrome (FXS). Mitochondria show plasticity in morphology and function in response to neuronal activity, and previous research has reported impairments in mitochondrial morphology and function in disease. We and others have previously reported abnormalities in distinct types of homeostatic plasticity in FXS. It remains unknown if or how activity deprivation triggering homeostatic plasticity affects mitochondria in axons and/or dendrites and whether impairments occur in neurodevelopmental disorders. Here, we test the hypothesis that mitochondria are structurally and functionally modified in a compartment-specific manner during homeostatic plasticity using a model of activity deprivation in cortical neurons from wild-type mice and that this plasticity-induced regulation is altered in Fmr1-knockout (KO) neurons. We uncovered dendrite-specific regulation of the mitochondrial surface area, whereas axon initial segment (AIS) mitochondria show changes in polarity; both responses are lost in the Fmr1 KO. Taken together, our results demonstrate impairments in mitochondrial plasticity in FXS, which has not previously been reported. These results suggest that mitochondrial dysregulation in FXS could contribute to abnormal neuronal plasticity, with broader implications to other neurodevelopmental disorders and therapeutic strategies.

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Assembly and Function of the Juxtaparanodal Kv1 Complex in Health and Disease

Life ◽

10.3390/life11010008 ◽

2020 ◽

Vol 11 (1) ◽

pp. 8

Author(s):

Delphine Pinatel ◽

Catherine Faivre-Sarrailh

Keyword(s):

Cell Adhesion ◽

Adhesion Molecules ◽

Cell Adhesion Molecules ◽

Initial Segment ◽

Axon Initial Segment ◽

Health And Disease ◽

Low Threshold ◽

Frequency Of Action Potentials ◽

And Function ◽

Spike Initiation

The precise axonal distribution of specific potassium channels is known to secure the shape and frequency of action potentials in myelinated fibers. The low-threshold voltage-gated Kv1 channels located at the axon initial segment have a significant influence on spike initiation and waveform. Their role remains partially understood at the juxtaparanodes where they are trapped under the compact myelin bordering the nodes of Ranvier in physiological conditions. However, the exposure of Kv1 channels in de- or dys-myelinating neuropathy results in alteration of saltatory conduction. Moreover, cell adhesion molecules associated with the Kv1 complex, including Caspr2, Contactin2, and LGI1, are target antigens in autoimmune diseases associated with hyperexcitability such as encephalitis, neuromyotonia, or neuropathic pain. The clustering of Kv1.1/Kv1.2 channels at the axon initial segment and juxtaparanodes is based on interactions with cell adhesion molecules and cytoskeletal linkers. This review will focus on the trafficking and assembly of the axonal Kv1 complex in the peripheral and central nervous system (PNS and CNS), during development, and in health and disease.

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Faculty Opinions recommendation of ATP-P2X7 Receptor Modulates Axon Initial Segment Composition and Function in Physiological Conditions and Brain Injury.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718306467.793493319 ◽

2014 ◽

Author(s):

Matthew Rasband

Keyword(s):

Brain Injury ◽

P2x7 Receptor ◽

Initial Segment ◽

Axon Initial Segment ◽

Physiological Conditions ◽

And Function

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A sticky situation: regulation and function of protein palmitoylation with a spotlight on the axon and axon initial segment

Neuronal Signaling ◽

10.1042/ns20210005 ◽

2021 ◽

Vol 5 (4) ◽

Author(s):

Andrey A. Petropavlovskiy ◽

Jordan A. Kogut ◽

Arshia Leekha ◽

Charlotte A. Townsend ◽

Shaun S. Sanders

Keyword(s):

Protein Trafficking ◽

Lipid Membranes ◽

Initial Segment ◽

Protein Targeting ◽

Neurological Diseases ◽

Axon Initial Segment ◽

Neuronal Proteins ◽

Dependent Protein ◽

Specific Proteins ◽

And Function

Abstract In neurons, the axon and axon initial segment (AIS) are critical structures for action potential initiation and propagation. Their formation and function rely on tight compartmentalisation, a process where specific proteins are trafficked to and retained at distinct subcellular locations. One mechanism which regulates protein trafficking and association with lipid membranes is the modification of protein cysteine residues with the 16-carbon palmitic acid, known as S-acylation or palmitoylation. Palmitoylation, akin to phosphorylation, is reversible, with palmitate cycling being mediated by substrate-specific enzymes. Palmitoylation is well-known to be highly prevalent among neuronal proteins and is well studied in the context of the synapse. Comparatively, how palmitoylation regulates trafficking and clustering of axonal and AIS proteins remains less understood. This review provides an overview of the current understanding of the biochemical regulation of palmitoylation, its involvement in various neurological diseases, and the most up-to-date perspective on axonal palmitoylation. Through a palmitoylation analysis of the AIS proteome, we also report that an overwhelming proportion of AIS proteins are likely palmitoylated. Overall, our review and analysis confirm a central role for palmitoylation in the formation and function of the axon and AIS and provide a resource for further exploration of palmitoylation-dependent protein targeting to and function at the AIS.

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