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The Neuroscientist : a Review Journal... Dec 2009Action potentials (APs) provide the primary means of rapid information transfer in the nervous system. Where exactly these signals are initiated in neurons has been a... (Review)
Review
Action potentials (APs) provide the primary means of rapid information transfer in the nervous system. Where exactly these signals are initiated in neurons has been a basic question in neurobiology and the subject of extensive study. Converging lines of evidence indicate that APs are initiated in a discrete and highly specialized portion of the axon-the axon initial segment (AIS). The authors review key aspects of the organization and function of the AIS and focus on recent work that has provided important insights into its electrical signaling properties. In addition to its main role in AP initiation, the new findings suggest that the AIS is also a site of complex AP modulation by specific types of ion channels localized to this axonal domain.
Topics: Action Potentials; Animals; Axons; Cell Membrane; Cell Shape; Electrophysiology; Humans; Ion Channels; Neural Inhibition; Potassium Channels; Sodium Channels; gamma-Aminobutyric Acid
PubMed: 20007821
DOI: 10.1177/1073858409341973 -
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 -
Current Opinion in Neurobiology Aug 2010The axon initial segment is a unique neuronal subregion involved in the initiation of action potentials and in the control of axonal identity. Recent work has helped our... (Review)
Review
The axon initial segment is a unique neuronal subregion involved in the initiation of action potentials and in the control of axonal identity. Recent work has helped our understanding of how this specialised structure develops, not least in identifying possible mechanisms leading to the localisation of the AIS's master organiser protein, ankyrin-G. The most exciting current work, however, focuses on later aspects of AIS function and plasticity. Recent studies have shown that the AIS is subdivided into distinct structural and functional domains, have demonstrated how the AIS acts as a cytoplasmic barrier for axonal transport, and have discovered that the AIS can be surprisingly plastic in its responses to alterations in neuronal activity.
Topics: Action Potentials; Animals; Ankyrins; Axons; Cell Adhesion Molecules; Extracellular Matrix; Models, Biological; Neurons; Sodium Channels; Spectrin
PubMed: 20537529
DOI: 10.1016/j.conb.2010.04.012 -
Brain : a Journal of Neurology Jun 2022The axon initial segment is a specialized compartment of the proximal axon of CNS neurons where action potentials are initiated. However, it remains unknown whether this...
The axon initial segment is a specialized compartment of the proximal axon of CNS neurons where action potentials are initiated. However, it remains unknown whether this domain is assembled in sensory dorsal root ganglion neurons, in which spikes are initiated in the peripheral terminals. Here we investigate whether sensory neurons have an axon initial segment and if it contributes to spontaneous activity in neuropathic pain. Our results demonstrate that myelinated dorsal root ganglion neurons assemble an axon initial segment in the proximal region of their stem axon, enriched in the voltage-gated sodium channels Nav1.1 and Nav1.7. Using correlative immunofluorescence and calcium imaging, we demonstrate that the Nav1.7 channels at the axon initial segment are associated with spontaneous activity. Computer simulations further indicate that the axon initial segment plays a key role in the initiation of spontaneous discharges by lowering their voltage threshold. Finally, using a Cre-based mouse model for time-controlled axon initial segment disassembly, we demonstrate that this compartment is a major source of spontaneous discharges causing mechanical allodynia in neuropathic pain. Thus, an axon initial segment domain is present in sensory neurons and facilitates their spontaneous activity. This study provides a new insight in the cellular mechanisms that cause pathological pain and identifies a new potential target for chronic pain management.
Topics: Animals; Axon Initial Segment; Ganglia, Spinal; Humans; Hyperalgesia; Mice; Neuralgia; Sensory Receptor Cells
PubMed: 35661858
DOI: 10.1093/brain/awac078 -
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 -
Visual Neuroscience 1995We have studied the glial investment of ganglion cells of the cat's retina, orienting the sections taken for electron microscopy so that the investment could be traced...
We have studied the glial investment of ganglion cells of the cat's retina, orienting the sections taken for electron microscopy so that the investment could be traced from the soma along the axon. The soma of each ganglion cell is covered by a close-fitting, continuous sheath formed by Müller cells. The axon hillock and the first part of the initial segment are invested by an extension of the somal sheath, and are thus enclosed in the same glial compartment as the soma. The initial segment extends a few microns past the Müller cell sheath; this last length of the initial segment is contacted by numerous processes of astrocytes, which converge on it in a pattern found also on nodes of the same axons, in the optic nerve. Beyond the initial segment, the intraretinal lengths of the axons are invested by both Müller cells and astrocytes, but the investment is strikingly incomplete. Large areas of axonal membrane have no glial cover, and lie close to other axonal membranes. The sequential arrangement of these distinct forms of glial wrapping of the soma, initial segment, and axon is described here for the first time. It is suggested that this pattern of glial investment controls the flow of current between dendrite and initial segment of the ganglion cell, defines the site of initiation of action spikes, and controls the formation of synapses on the soma and initial segment.
Topics: Action Potentials; Animals; Astrocytes; Axons; Cats; Neuroglia; Optic Nerve; Retinal Ganglion Cells
PubMed: 7786848
DOI: 10.1017/s0952523800007951 -
The Journal of Neuroscience : the... Dec 1985The axoplasmic reticulum (AR) and the discrete element (e.g., vesicles, vesiculotubular bodies, multivesicular bodies, etc.) constitute the endomembrane system of the...
The axoplasmic reticulum (AR) and the discrete element (e.g., vesicles, vesiculotubular bodies, multivesicular bodies, etc.) constitute the endomembrane system of the axon. It is reported here that the AR of bullfrog sciatic nerve readily fills with osmium deposits during osmium impregnation. In contrast, the discrete elements and mitochondria are highly resistant to impregnation. Hence this preparation is well suited to address the nature of possible interactions between AR and rough endoplasmic reticulum (RER) in the axon hillock. It is also ideal to study the origin of the axonal discrete elements within the cell body as well as their interaction with other somal endomembrane system components. Tissues used in the present study were spinal ganglia, sciatic nerve, and spinal roots from Rana catesbeiana. Thick sections (1 to 2 microm) of this material were studied by high voltage electron microscopy. In some cases, osmium impregnation was followed by en bloc staining with lead aspartate. This made visible membranous structures that had not filled with osmium deposits during impregnation. Serial 170-nm-thick sections of this latter material were prepared and serial stereo pair electron micrographs of axon hillocks were collected. These were used to reconstruct three-dimensionally the AR and to study its relationship with RER and with discrete elements. The impregnated AR within the axon hillock was found to terminate as many proximally pointing finger-like projections. A large portion of these projections were found to form connections with RER. Some, however, terminated as true blind endings. Single unimpregnated discrete cisternae were found throughout the cytoplasm of the cell body, axon hillock, and axon. Large clusters of unimpregnated vesicles were usually found in close association with the trans face of the Golgi apparatus. These results indirectly support the hypothesis that vectors of fast axonal transport, namely the discrete elements, form directly at the trans face of the Golgi apparatus. From here they move toward and subsequently down the axon without any membrane fission-fusion events with either RER or AR. AR, although it forms continuities with RER, retains a distinctly different chemical composition from RER as evidenced by its much higher affinity for osmium. Thus, it should be considered as an endomembrane component separate from, although intimately related to the RER.
Topics: Animals; Axons; Endoplasmic Reticulum; Ganglia, Spinal; Golgi Apparatus; Intracellular Membranes; Microscopy, Electron; Myelin Sheath; Neurons; Rana catesbeiana; Sciatic Nerve; Spinal Nerve Roots
PubMed: 3878394
DOI: 10.1523/JNEUROSCI.05-12-03135.1985 -
Nature Sep 1966
Topics: Animals; Axons; Cattle; Microscopy, Electron; Vestibular Nuclei
PubMed: 5970111
DOI: 10.1038/2111101a0 -
The Neuroscientist : a Review Journal... Jun 2015The axon initial segment (AIS) is a specialized axonal compartment that is involved in conversion of synaptic potentials into action potentials. Recent studies revealed... (Review)
Review
The axon initial segment (AIS) is a specialized axonal compartment that is involved in conversion of synaptic potentials into action potentials. Recent studies revealed that structural properties of the AIS, such as length and position relative to the soma, are differentiated in a cell-specific manner and shape signal processing of individual neurons. Moreover, these structural properties are not fixed but vary in response to prolonged changes of neuronal activity, which readjusts action potential threshold and compensates for the changes of activity, indicating that this structural plasticity of the AIS works as a homeostatic mechanism and contributes to maintain neuronal activity. Neuronal activity plays a crucial role in formation, maintenance, and refinement of neural circuits as well as in pathogenesis and/or pathophysiology of diseases. Thus, this plasticity should be a key to understand physiology and pathology of the brain.
Topics: Action Potentials; Animals; Axons; Brain; Homeostasis; Humans; Models, Neurological; Neuronal Plasticity; Neurons
PubMed: 24847046
DOI: 10.1177/1073858414535986 -
The Journal of Experimental Biology Feb 2015Polarized distribution of signaling molecules to axons and dendrites facilitates directional information flow in complex vertebrate nervous systems. The topic we address... (Review)
Review
Polarized distribution of signaling molecules to axons and dendrites facilitates directional information flow in complex vertebrate nervous systems. The topic we address here is when the key aspects of neuronal polarity evolved. All neurons have a central cell body with thin processes that extend from it to cover long distances, and they also all rely on voltage-gated ion channels to propagate signals along their length. The most familiar neurons, those in vertebrates, have additional cellular features that allow them to send directional signals efficiently. In these neurons, dendrites typically receive signals and axons send signals. It has been suggested that many of the distinct features of axons and dendrites, including the axon initial segment, are found only in vertebrates. However, it is now becoming clear that two key cytoskeletal features that underlie polarized sorting, a specialized region at the base of the axon and polarized microtubules, are found in invertebrate neurons as well. It thus seems likely that all bilaterians generate axons and dendrites in the same way. As a next step, it will be extremely interesting to determine whether the nerve nets of cnidarians and ctenophores also contain polarized neurons with true axons and dendrites, or whether polarity evolved in concert with the more centralized nervous systems found in bilaterians.
Topics: Animals; Axons; Biological Evolution; Cytoskeleton; Dendrites; Invertebrates; Microtubules; Neurons
PubMed: 25696820
DOI: 10.1242/jeb.112359