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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 -
Journal of Neurocytology Oct 1985Analysis of the plasmalemma of frog dorsal root ganglion cells by freeze-fracture demonstrates regional differences in the distribution of intramembranous particles....
Analysis of the plasmalemma of frog dorsal root ganglion cells by freeze-fracture demonstrates regional differences in the distribution of intramembranous particles. Although P-face particles are distributed rather uniformly, the E-face particle concentration at the cell body (approximately 300 micron -2) is much lower than that at the axon hillock (approximately 900 micron -2), proximal initial segment (approximately 1000 micron -2), or intermediate portion of the initial segment (approximately 800 micron -2). The particle concentrations in the latter regions approach that at the node of Ranvier and, moreover, particle size analysis reveals that the E-face particles, like those at the node, include a large number that are 10 nm or more in diameter. Thin sections reveal patches of a dense undercoating on the cytoplasmic surface of the axolemma in some regions of the initial segment but not the axon hillock. It is concluded from these results that the axon hillock and the initial segment of dorsal root ganglion cells have some of the structural characteristics of the node of Ranvier.
Topics: Animals; Axons; Cell Membrane; Freeze Fracturing; Ganglia, Spinal; Intracellular Membranes; Ion Channels; Microscopy, Electron; Neurons, Afferent; Rana pipiens; Sodium
PubMed: 2419519
DOI: 10.1007/BF01170825 -
Neuron Oct 2019The axon initial segment (AIS) is a unique neuronal compartment that plays a crucial role in the generation of action potential and neuronal polarity. The assembly of...
The axon initial segment (AIS) is a unique neuronal compartment that plays a crucial role in the generation of action potential and neuronal polarity. The assembly of the AIS requires membrane, scaffolding, and cytoskeletal proteins, including Ankyrin-G and TRIM46. How these components cooperate in AIS formation is currently poorly understood. Here, we show that Ankyrin-G acts as a scaffold interacting with End-Binding (EB) proteins and membrane proteins such as Neurofascin-186 to recruit TRIM46-positive microtubules to the plasma membrane. Using in vitro reconstitution and cellular assays, we demonstrate that TRIM46 forms parallel microtubule bundles and stabilizes them by acting as a rescue factor. TRIM46-labeled microtubules drive retrograde transport of Neurofascin-186 to the proximal axon, where Ankyrin-G prevents its endocytosis, resulting in stable accumulation of Neurofascin-186 at the AIS. Neurofascin-186 enrichment in turn reinforces membrane anchoring of Ankyrin-G and subsequent recruitment of TRIM46-decorated microtubules. Our study reveals feedback-based mechanisms driving AIS assembly.
Topics: Animals; Ankyrins; Axon Initial Segment; Axonal Transport; COS Cells; Cell Adhesion Molecules; Cell Line, Tumor; Chlorocebus aethiops; Cytoskeleton; Endocytosis; Feedback, Physiological; HEK293 Cells; Hippocampus; Humans; Microtubule-Associated Proteins; Microtubules; Nerve Growth Factors; Neurons; Rats; Tripartite Motif Proteins
PubMed: 31474508
DOI: 10.1016/j.neuron.2019.07.029 -
Current Opinion in Neurobiology Jun 2008Action potential initiation, modulation, and duration in neurons depend on a variety of Na+ and K+ channels that are highly enriched at the axon initial segment (AIS).... (Review)
Review
Action potential initiation, modulation, and duration in neurons depend on a variety of Na+ and K+ channels that are highly enriched at the axon initial segment (AIS). The AIS also has high densities of cell adhesion molecules (CAMs), modulatory proteins, and a unique extracellular matrix (ECM). In contrast to other functional domains of axons (e.g. the nodes of Ranvier and axon terminals) whose development depends on the interactions with different cells (e.g. myelinating glia and postsynaptic cells), the recruitment and retention of AIS proteins is intrinsically specified through axonal cytoskeletal and scaffolding proteins. We speculate that the AIS has previously unappreciated forms of plasticity that influence neuronal excitability, and that AIS plasticity is regulated by the developmental or activity-dependent modulation of scaffolding protein levels rather than directly altering ion channel expression.
Topics: Action Potentials; Animals; Axons; Cell Adhesion Molecules; Cytoskeleton; Extracellular Matrix; Nerve Tissue Proteins; Presynaptic Terminals
PubMed: 18801432
DOI: 10.1016/j.conb.2008.08.008 -
Handbook of Clinical Neurology 2022To adapt to the sustained demands of chronic stress, discrete brain circuits undergo structural and functional changes often resulting in anxiety disorders. In some... (Review)
Review
To adapt to the sustained demands of chronic stress, discrete brain circuits undergo structural and functional changes often resulting in anxiety disorders. In some individuals, anxiety disorders precede the development of motor symptoms of Parkinson's disease (PD) caused by degeneration of neurons in the substantia nigra (SN). Here, we present a circuit framework for probing a causal link between chronic stress, anxiety, and PD, which postulates a central role of abnormal neuromodulation of the SN's axon initial segment by brainstem inputs. It is grounded in findings demonstrating that the earliest PD pathologies occur in the stress-responsive, emotion regulation network of the brainstem, which provides the SN with dense aminergic and cholinergic innervation. SN's axon initial segment (AIS) has unique features that support the sustained and bidirectional propagation of activity in response to synaptic inputs. It is therefore, especially sensitive to circuit-mediated stress-induced imbalance of neuromodulation, and thus a plausible initiating site of neurodegeneration. This could explain why, although secondary to pathophysiologies in other brainstem nuclei, SN degeneration is the most extensive. Consequently, the cardinal symptom of PD, severe motor deficits, arise from degeneration of the nigrostriatal pathway rather than other brainstem nuclei. Understanding when and how circuit dysfunctions underlying anxiety can progress to neurodegeneration, raises the prospect of timed interventions for reversing, or at least impeding, the early pathophysiologies that lead to PD and possibly other neurodegenerative disorders.
Topics: Anxiety; Anxiety Disorders; Axon Initial Segment; Humans; Parkinson Disease; Substantia Nigra
PubMed: 35034756
DOI: 10.1016/B978-0-12-819410-2.00025-4 -
Brain Research Mar 1982Seventeen neurons which were postsynaptic to axon collateral boutons of intracellularly HRP-stained triceps surae alpha-motoneurons were studied ultrastructurally. All...
Seventeen neurons which were postsynaptic to axon collateral boutons of intracellularly HRP-stained triceps surae alpha-motoneurons were studied ultrastructurally. All 17 neurons were situated in lamina VII, ventro-medially to the main motor nuclei. This and other facts support the assumption that the observed neurons are morphological correlates to the physiologically defined Renshaw cells. The contours of the cell bodies, as observed in the midnucleolus plane, were elongated. The axons originated either from the cell bodies or from dendrites. The number of dendrites of each neuron varied between 3 and 7. The appearance of the presumed Renshaw cells was also compared with that of a larger sample of neurons from the ventral part of lamina VII which was studied light microscopically in semithin sections. It was suggested that the Renshaw cells belong to the larger and more elongated neurons in the area.
Topics: Animals; Axons; Cats; Dendrites; Interneurons; Microscopy, Electron; Spinal Cord
PubMed: 7188315
DOI: 10.1016/0006-8993(82)90192-5 -
The Journal of Neuroscience : the... Oct 2022The axon initial segment (AIS) generates action potentials and maintains neuronal polarity by regulating the differential trafficking and distribution of proteins,...
The axon initial segment (AIS) generates action potentials and maintains neuronal polarity by regulating the differential trafficking and distribution of proteins, transport vesicles, and organelles. Injury and disease can disrupt the AIS, and the subsequent loss of clustered ion channels and polarity mechanisms may alter neuronal excitability and function. However, the impact of AIS disruption on axon regeneration after injury is unknown. We generated male and female mice with AIS-deficient multipolar motor neurons by deleting AnkyrinG, the master scaffolding protein required for AIS assembly and maintenance. We found that after nerve crush, neuromuscular junction reinnervation was significantly delayed in AIS-deficient motor neurons compared with control mice. In contrast, loss of AnkyrinG from pseudo-unipolar sensory neurons did not impair axon regeneration into the intraepidermal nerve fiber layer. Even after AIS-deficient motor neurons reinnervated the neuromuscular junction, they failed to functionally recover because of reduced synaptic vesicle protein 2 at presynaptic terminals. In addition, mRNA trafficking was disrupted in AIS-deficient axons. Our results show that, after nerve injury, an intact AIS is essential for efficient regeneration and functional recovery of axons in multipolar motor neurons. Our results also suggest that loss of polarity in AIS-deficient motor neurons impairs the delivery of axonal proteins, mRNAs, and other cargoes necessary for regeneration. Thus, therapeutic strategies for axon regeneration must consider preservation or reassembly of the AIS. Disruption of the axon initial segment is a common event after nervous system injury. For multipolar motor neurons, we show that axon initial segments are essential for axon regeneration and functional recovery after injury. Our results may help explain injuries where axon regeneration fails, and suggest strategies to promote more efficient axon regeneration.
Topics: Male; Female; Mice; Animals; Axons; Axon Initial Segment; Ankyrins; Nerve Regeneration; Synapses; Ion Channels; Motor Neurons; RNA, Messenger
PubMed: 36096668
DOI: 10.1523/JNEUROSCI.1261-22.2022 -
Neuroscience Feb 1993The cytoplasm of the highly polarized nerve cell is permanently segregated into domains with differing organellar composition. The mechanisms maintaining this...
The cytoplasm of the highly polarized nerve cell is permanently segregated into domains with differing organellar composition. The mechanisms maintaining this segregation are largely unknown. In order to elucidate the potential role of cytoskeletal elements in this process we compared the cytoplasmic segregation within the giant electromotoneuron of the electric catfish (Malapterurus electricus) with the distribution of binding sites for antibodies against elements of the cytoskeleton. Most prominent cytoplasmic segregations include the formation of a subplasmalemmal cortical structure free of Nissl bodies and Golgi cisternae, the separation within the soma of domains containing rough endoplasmic reticulum and filament-rich domains, and the soma-axon transition. The cytoplasmic transition at the axon hillock forms a distinct borderline where Nissl bodies, Golgi cisternae and the bulk of lysosomes abruptly terminate and are excluded from the axoplasm. Synaptic vesicles and mitochondria are free to pass compartmental borders. Tropomyosin, spectrin, and alpha-actinin reveal a rather homogeneous immunofluorescence throughout the neuron. In contrast, neurofilament protein and tubulin display a distinctly increased immunofluorescence in the subplasmalemmal cortical layer, in dendrites as well as in the axon. The increase in immunofluorescence at the axon hillock exactly depicts the small transition zone from the somatic cytoplasm rich in Nissl bodies, Golgi cisternae and lysosomes to the differently structured axoplasm. The picture is similar for beta-tubulin, tyrosinylated and detyrosinylated alpha-tubulin. Detyrosinylated tubulin (glu-tubulin, which is contained in microtubules of increased stability) shows the most prominent enrichment in the axon. The distribution of myosin is comparable to that of neurofilament protein but there is less difference in immunofluorescence between the domains. Our results would be compatible with a role of microtubules together with (the closely associated) neurofilaments in the segregation of neuronal cytoplasmic domains. Active transport as well as stable binding to the somatic cytoskeleton might counteract a homogeneous cytoplasmic distribution of the various classes of organelles by diffusion.
Topics: Actinin; Animals; Antibodies, Monoclonal; Axons; Binding Sites, Antibody; Catfishes; Cytoplasm; Cytoskeleton; Fluorescent Antibody Technique; Golgi Apparatus; Lysosomes; Microscopy, Electron; Microscopy, Immunoelectron; Mitochondria; Motor Neurons; Myosins; Organelles; Spectrin; Synaptic Vesicles; Tropomyosin
PubMed: 8450971
DOI: 10.1016/0306-4522(93)90423-d -
Experimental Neurology May 2016Transection of nerve axons (axotomy) leads to rapid (Wallerian) degeneration of the distal portion of the severed axon whereas the proximal portion and the soma often...
Transection of nerve axons (axotomy) leads to rapid (Wallerian) degeneration of the distal portion of the severed axon whereas the proximal portion and the soma often survive. Clinicians and neuroscientists have known for decades that somal survival is less likely for cells transected nearer to the soma, compared to further from the soma. Calcium ion (Ca(2+)) influx at the cut axonal end increases somal Ca(2+) concentration, which subsequently activates apoptosis and other pathways that lead to cell death. The same Ca(2+) influx activates parallel pathways that seal the plasmalemma, reduce Ca(2+) influx, and thereby enable the soma to survive. In this study, we have examined the ability of transected B104 axons to seal, as measured by uptake or exclusion of fluorescent dye, and quantified the relationship between sealing frequency and transection distance from the axon hillock. We report that sealing frequency is maximal at about 150μm (μm) from the axon hillock and decreases exponentially with decreasing transection distance with a space constant of about 40μm. We also report that after Ca(2+) influx is initiated, the curve of sealing frequency versus time is well-fit by a one-phase, rising exponential model having a time constant of several milliseconds that is longer nearer to, versus further from, the axon hillock. These results could account for the increased frequency of cell death for axotomies nearer to, versus farther from, the soma of many types of neurons.
Topics: Animals; Apoptosis; Axons; Axotomy; Calcium; Calcium Signaling; Cell Line, Tumor; Cell Membrane; Fluorescent Dyes; Models, Neurological; Neurites; Neurons; Rats
PubMed: 26851541
DOI: 10.1016/j.expneurol.2016.02.001 -
PloS One 2021The axon initial segment (AIS) responsible for action potential initiation is a dynamic structure that varies and changes together with neuronal excitability. Like other...
The axon initial segment (AIS) responsible for action potential initiation is a dynamic structure that varies and changes together with neuronal excitability. Like other neuron types, alpha motoneurons in the mammalian spinal cord express heterogeneity and plasticity in AIS geometry, including length (AISl) and distance from soma (AISd). The present study aimed to establish the relationship of AIS geometry with a measure of intrinsic excitability, rheobase current, that varies by 20-fold or more among normal motoneurons. We began by determining whether AIS length or distance differed for motoneurons in motor pools that exhibit different activity profiles. Motoneurons sampled from the medial gastrocnemius (MG) motor pool exhibited values for average AISd that were significantly greater than that for motoneurons from the soleus (SOL) motor pool, which is more readily recruited in low-level activities. Next, we tested whether AISd covaried with intrinsic excitability of individual motoneurons. In anesthetized rats, we measured rheobase current intracellularly from MG motoneurons in vivo before labeling them for immunohistochemical study of AIS structure. For 16 motoneurons sampled from the MG motor pool, this combinatory approach revealed that AISd, but not AISl, was significantly related to rheobase, as AIS tended to be located further from the soma on motoneurons that were less excitable. Although a causal relation with excitability seems unlikely, AISd falls among a constellation of properties related to the recruitability of motor units and their parent motoneurons.
Topics: Action Potentials; Animals; Axon Initial Segment; Axons; Electrophysiology; Male; Motor Neurons; Muscles; Neural Conduction; Neurons, Efferent; Rats; Rats, Wistar; Spinal Cord
PubMed: 34797870
DOI: 10.1371/journal.pone.0259918