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Cells Aug 2020By binding to actin filaments, non-muscle myosin II (NMII) generates actomyosin networks that hold unique contractile properties. Their dynamic nature is essential for... (Review)
Review
By binding to actin filaments, non-muscle myosin II (NMII) generates actomyosin networks that hold unique contractile properties. Their dynamic nature is essential for neuronal biology including the establishment of polarity, growth cone formation and motility, axon growth during development (and axon regeneration in the adult), radial and longitudinal axonal tension, and synapse formation and function. In this review, we discuss the current knowledge on the spatial distribution and function of the actomyosin cytoskeleton in different axonal compartments. We highlight some of the apparent contradictions and open questions in the field, including the role of NMII in the regulation of axon growth and regeneration, the possibility that NMII structural arrangement along the axon shaft may control both radial and longitudinal contractility, and the mechanism and functional purpose underlying NMII enrichment in the axon initial segment. With the advances in live cell imaging and super resolution microscopy, it is expected that in the near future the spatial distribution of NMII in the axon, and the mechanisms by which it participates in axonal biology will be further untangled.
Topics: Axons; Growth Cones; Humans
PubMed: 32858875
DOI: 10.3390/cells9091961 -
Frontiers in Psychiatry 2022Parvalbumin (PV) is a calcium binding protein expressed by inhibitory fast-spiking interneurons in the cerebral cortex. By generating a fast stream of action potentials,... (Review)
Review
Parvalbumin (PV) is a calcium binding protein expressed by inhibitory fast-spiking interneurons in the cerebral cortex. By generating a fast stream of action potentials, PV+ interneurons provide a quick and stable inhibitory input to pyramidal neurons and contribute to the generation of gamma oscillations in the cortex. Their fast-firing rates, while advantageous for regulating cortical signaling, also leave them vulnerable to metabolic stress. Chandelier (Ch) cells are a type of PV+ interneuron that modulate the output of pyramidal neurons and synchronize spikes within neuron populations by directly innervating the pyramidal axon initial segment. Changes in the morphology and/or function of PV+ interneurons, mostly of Ch cells, are linked to neurological disorders. In ASD, the number of PV+ Ch cells is decreased across several cortical areas. Changes in the morphology and/or function of PV+ interneurons have also been linked to schizophrenia, epilepsy, and bipolar disorder. Herein, we review the role of PV and PV+ Ch cell alterations in ASD and other psychiatric disorders.
PubMed: 36311505
DOI: 10.3389/fpsyt.2022.913550 -
Communications Physics 2020Sensing neuronal action potential associated magnetic fields (APMFs) is an emerging viable alternative of functional brain mapping. Measurement of APMFs of large axons...
Sensing neuronal action potential associated magnetic fields (APMFs) is an emerging viable alternative of functional brain mapping. Measurement of APMFs of large axons of worms have been possible due to their size. In the mammalian brain, axon sizes, their numbers and routes, restricts using such functional imaging methods. With a segmented model of mammalian pyramidal neurons, we show that the APMF of intra-axonal currents in the axon hillock are two orders of magnitude larger than other neuronal locations. Expected 2D magnetic field maps of naturalistic spiking activity of a volume of neurons via widefield diamond-nitrogen-vacancy-center-magnetometry were simulated. A dictionary-based matching pursuit type algorithm applied to the data using the axon-hillock's APMF signature allowed spatiotemporal reconstruction of action potentials in the volume of brain tissue at single cell resolution. Enhancement of APMF signals coupled with magnetometry advances thus can potentially replace current functional brain mapping techniques.
PubMed: 33072889
DOI: 10.1038/s42005-020-00439-6 -
ELife Jan 2024Detailed characterization of interneuron types in primary visual cortex (V1) has greatly contributed to understanding visual perception, yet the role of chandelier cells...
Detailed characterization of interneuron types in primary visual cortex (V1) has greatly contributed to understanding visual perception, yet the role of chandelier cells (ChCs) in visual processing remains poorly characterized. Using viral tracing we found that V1 ChCs predominantly receive monosynaptic input from local layer 5 pyramidal cells and higher-order cortical regions. Two-photon calcium imaging and convolutional neural network modeling revealed that ChCs are visually responsive but weakly selective for stimulus content. In mice running in a virtual tunnel, ChCs respond strongly to events known to elicit arousal, including locomotion and visuomotor mismatch. Repeated exposure of the mice to the virtual tunnel was accompanied by reduced visual responses of ChCs and structural plasticity of ChC boutons and axon initial segment length. Finally, ChCs only weakly inhibited pyramidal cells. These findings suggest that ChCs provide an arousal-related signal to layer 2/3 pyramidal cells that may modulate their activity and/or gate plasticity of their axon initial segments during behaviorally relevant events.
Topics: Animals; Mice; Neurons; Pyramidal Cells; Visual Cortex; Interneurons; Arousal
PubMed: 38192196
DOI: 10.7554/eLife.91153 -
The Journal of Cell Biology Jul 2020The 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...
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.
Topics: Animals; Axons; Cytoskeleton; Intermediate Filaments; Interneurons; Invertebrates; Microtubules; Motor Neurons; Neuronal Plasticity; Sensory Receptor Cells; Vertebrates
PubMed: 32369543
DOI: 10.1083/jcb.201912081 -
Mathematical Biosciences Nov 2020By assuming that tau protein can be in seven kinetic states, we developed a model of tau protein transport in the axon and in the axon initial segment (AIS). Two...
By assuming that tau protein can be in seven kinetic states, we developed a model of tau protein transport in the axon and in the axon initial segment (AIS). Two separate sets of kinetic constants were determined, one in the axon and the other in the AIS. This was done by fitting the model predictions in the axon with experimental results and by fitting the model predictions in the AIS with the assumed linear increase of the total tau concentration in the AIS. The calibrated model was used to make predictions about tau transport in the axon and in the AIS. To the best of our knowledge, this is the first paper that presents a mathematical model of tau transport in the AIS. Our modeling results suggest that binding of free tau to microtubules creates a negative gradient of free tau in the AIS. This leads to diffusion-driven tau transport from the soma into the AIS. The model further suggests that slow axonal transport and diffusion-driven transport of tau work together in the AIS, moving tau anterogradely. Our numerical results predict an interplay between these two mechanisms: as the distance from the soma increases, the diffusion-driven transport decreases, while motor-driven transport becomes larger. Thus, the machinery in the AIS works as a pump, moving tau into the axon.
Topics: Alzheimer Disease; Animals; Axon Initial Segment; Axonal Transport; Axons; Biological Transport, Active; Computer Simulation; Diffusion; Humans; Kinetics; Mathematical Concepts; Microtubules; Models, Neurological; tau Proteins
PubMed: 32920097
DOI: 10.1016/j.mbs.2020.108468 -
Current Protocols in Neuroscience Sep 2019The axon initial segment (AIS) is the first 20- to 60-μm segment of the axon proximal to the soma of a neuron. This highly specialized subcellular domain is the...
The axon initial segment (AIS) is the first 20- to 60-μm segment of the axon proximal to the soma of a neuron. This highly specialized subcellular domain is the initiation site of the action potential and contains a high concentration of voltage-gated ion channels held in place by a complex nexus of scaffolding and regulatory proteins that ensure proper electrical activity of the neuron. Studies have shown that dysfunction of many AIS channels and scaffolding proteins occurs in a variety of neuropsychiatric and neurodegenerative diseases, raising the need to develop accurate methods for visualization and quantification of the AIS and its protein content in models of normal and disease conditions. In this article, we describe methods for immunolabeling AIS proteins in cultured neurons and brain slices as well as methods for quantifying protein expression and pattern distribution using fluorescent labeling of these proteins. © 2019 by John Wiley & Sons, Inc.
Topics: Action Potentials; Animals; Axon Initial Segment; Axons; Brain; Cells, Cultured; Neuroimaging; Neurons
PubMed: 31532918
DOI: 10.1002/cpns.78 -
The Journal of Neuroscience : the... Feb 2022The axon initial segment (AIS), nodes of Ranvier, and the oligodendrocyte-derived myelin sheath have significant influence on the firing patterns of neurons and the...
The axon initial segment (AIS), nodes of Ranvier, and the oligodendrocyte-derived myelin sheath have significant influence on the firing patterns of neurons and the faithful, coordinated transmission of action potentials (APs) to downstream brain regions. In the olfactory bulb (OB), olfactory discrimination tasks lead to adaptive changes in cell firing patterns, and the output signals must reliably travel large distances to other brain regions along highly myelinated tracts. Whether myelinated axons adapt to facilitate olfactory sensory processing is unknown. Here, we investigate the morphology and physiology of mitral cell (MC) axons in the olfactory system of adult male and female mice and show that unilateral sensory deprivation causes system-wide adaptations in axonal morphology and myelin thickness. MC spiking patterns and APs also adapted to sensory deprivation. Strikingly, myelination and MC physiology were altered on both the deprived and nondeprived sides, indicating system level adaptations to reduced sensory input. Our work demonstrates a previously unstudied mechanism of plasticity in the olfactory system. Successful transmission of information from the olfactory bulb (OB) to piriform cortex through the lateral olfactory tract (LOT) relies on synchronized arrival of action potentials (APs). The coincident arrival of APs is dependent on reliable generation of APs in the axon initial segment (AIS) and fast conduction mediated by axon myelination. Here, we studied changes in mitral cell (MC) firing and AIS structure as well as changes in myelination of the LOT on unilateral olfactory deprivation in the adult mouse. Strikingly, myelination and MC physiology were altered on both the deprived and nondeprived sides, indicating system level adaptations to reduced sensory input. Our work demonstrates a previously unstudied mechanism of plasticity in the olfactory system.
Topics: Animals; Axons; Female; Male; Mice; Myelin Sheath; Olfactory Bulb; Sensory Deprivation; Smell
PubMed: 35022219
DOI: 10.1523/JNEUROSCI.0305-21.2021 -
Developmental Biology Jun 2022Many neurons in bilaterian animals are polarized with functionally distinct axons and dendrites. Microtubule polarity, microtubule stability, and the axon initial...
Many neurons in bilaterian animals are polarized with functionally distinct axons and dendrites. Microtubule polarity, microtubule stability, and the axon initial segment (AIS) have all been shown to influence polarized transport in neurons. Each of these cytoskeletal cues could act independently to control axon and dendrite identity, or there could be a hierarchy in which one acts upstream of the others. Here we test the hypothesis that microtubule polarity acts as a master regulator of neuronal polarity by using a Drosophila genetic background in which some dendrites have normal minus-end-out microtubule polarity and others have the axonal plus-end-out polarity. In these mosaic dendrite arbors, we found that ribosomes, which are more abundant in dendrites than axons, were reduced in plus-end-out dendrites, while an axonal cargo was increased. In addition, we determined that microtubule stability was different in plus-end-out and minus-end-out dendrites, with plus-end-out ones having more stable microtubules like axons. Similarly, we found that ectopic diffusion barriers, like those at the AIS, formed at the base of dendrites with plus-end-out regions. Thus, changes in microtubule polarity were sufficient to rearrange other cytoskeletal features associated with neuronal polarization. However, overall neuron shape was maintained with only subtle changes in branching in mosaic arbors. We conclude that microtubule polarity can act upstream of many aspects of intracellular neuronal polarization, but shape is relatively resilient to changes in microtubule polarity in vivo.
Topics: Animals; Axons; Cell Polarity; Dendrites; Drosophila; Microtubules; Neurons
PubMed: 35341730
DOI: 10.1016/j.ydbio.2022.03.009 -
Neuron Aug 2020Identifying effective treatments for Alzheimer's disease (AD) has proven challenging and has instigated a shift in AD research focus toward the earliest... (Review)
Review
Identifying effective treatments for Alzheimer's disease (AD) has proven challenging and has instigated a shift in AD research focus toward the earliest disease-initiating cellular mechanisms. A key insight has been an increase in soluble Aβ oligomers in early AD that is causally linked to neuronal and circuit hyperexcitability. However, other accumulating AD-related peptides and proteins, including those derived from the same amyloid precursor protein, such as Aη or sAPPα, and autonomously, such as tau, exhibit surprising opposing effects on circuit dynamics. We propose that the effects of these on neuronal circuits have profound implications for our understanding of disease complexity and heterogeneity and for the development of personalized diagnostic and therapeutic strategies in AD. Here, we highlight important peptide-specific mechanisms of dynamic pathological disequilibrium of cellular and circuit activity in AD and discuss approaches in which these may be further understood, and theoretically and experimentally leveraged, to elucidate AD pathophysiology.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Astrocytes; Axon Initial Segment; Brain; Humans; Microglia; NAV1.1 Voltage-Gated Sodium Channel; Neural Pathways; Neurons; Peptide Fragments; Receptors, Glutamate; Seizures; Synapses; tau Proteins
PubMed: 32579881
DOI: 10.1016/j.neuron.2020.06.005