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Journal of Theoretical Biology Aug 2022Even though most axonal cargos are synthesized in the soma, the concentration of many of these cargos is larger at the presynaptic terminal than in the soma. This...
Even though most axonal cargos are synthesized in the soma, the concentration of many of these cargos is larger at the presynaptic terminal than in the soma. This requires transport of these cargos from the soma to the presynaptic terminal or other active sites in the axon. Axons utilize both bidirectional (for example, slow axonal transport) and unidirectional (for example, fast anterograde axonal transport) modes of cargo transport. Bidirectional transport seems to be less efficient because it requires more time and takes more energy to deliver cargos. In this paper, we studied a family of models which differ by the modes of axonal cargo transport (such as anterograde and retrograde motor-driven transport and passive diffusion) as well as by the presence or absence of pausing states. The models are studied to investigate their ability to describe axonal transport against the cargo concentration gradient. We argue that bidirectional axonal transport is described by a higher-order mathematical model, which allows imposing cargo concentration not only at the axon hillock but also at the axon terminal. The unidirectional transport model allows only for the imposition of cargo concentration at the axon hillock. Due to the great lengths of the axons, anterograde transport mostly relies on molecular motors, such as kinesins, to deliver cargos synthesized in the soma to the terminal and other active sites in the axon. Retrograde transport can be also motor-driven, in which case cargos are transported by dynein motors. If cargo concentration at the axon tip is higher than at the axon hillock, retrograde transport can also occur by cargo diffusion. However, because many axonal cargos are large or they assemble in multiprotein complexes for axonal transport, the diffusivity of such cargos is very small. We investigated the case of a small cargo diffusivity using a perturbation technique and found that for this case the effect of diffusion is limited to a very thin diffusion boundary layer near the axon tip. If cargo diffusivity is decreased in the model, we show that without motor-driven retrograde transport the model is unable to describe a high cargo concentration at the axon tip. To the best of our knowledge, our paper presents the first explanation for the utilization of seemingly inefficient bidirectional transport in neurons.
Topics: Axonal Transport; Axons; Dyneins; Kinesins; Neurons
PubMed: 35569529
DOI: 10.1016/j.jtbi.2022.111161 -
Nature Reviews. Neuroscience Oct 2017Neurons are akin to modern cities in that both are dependent on robust transport mechanisms. Like the best mass transit systems, trafficking in neurons must be tailored... (Review)
Review
Neurons are akin to modern cities in that both are dependent on robust transport mechanisms. Like the best mass transit systems, trafficking in neurons must be tailored to respond to local requirements. Neurons depend on both high-speed, long-distance transport and localized dynamics to correctly deliver cargoes and to tune synaptic responses. Here, we focus on the mechanisms that provide localized regulation of the transport machinery, including the cytoskeleton and molecular motors, to yield compartment-specific trafficking in the axon initial segment, axon terminal, dendrites and spines. The synthesis of these mechanisms provides a sophisticated and responsive transit system for the cell.
Topics: Animals; Biological Transport; Cytoskeleton; Humans; Models, Neurological; Molecular Motor Proteins; Neurons
PubMed: 28855741
DOI: 10.1038/nrn.2017.100 -
Frontiers in Cellular Neuroscience 2017Neurons are highly specialized cells of the nervous system that receive, process and transmit electrical signals critical for normal brain function. Here, we review the... (Review)
Review
Neurons are highly specialized cells of the nervous system that receive, process and transmit electrical signals critical for normal brain function. Here, we review the intricate organization of axonal membrane domains that facilitate rapid action potential conduction underlying communication between complex neuronal circuits. Two critical excitable domains of vertebrate axons are the axon initial segment (AIS) and the nodes of Ranvier, which are characterized by the high concentrations of voltage-gated ion channels, cell adhesion molecules and specialized cytoskeletal networks. The AIS is located at the proximal region of the axon and serves as the site of action potential initiation, while nodes of Ranvier, gaps between adjacent myelin sheaths, allow rapid propagation of the action potential through saltatory conduction. The AIS and nodes of Ranvier are assembled by ankyrins, spectrins and their associated binding partners through the clustering of membrane proteins and connection to the underlying cytoskeleton network. Although the AIS and nodes of Ranvier share similar protein composition, their mechanisms of assembly are strikingly different. Here we will cover the mechanisms of formation and maintenance of these axonal excitable membrane domains, specifically highlighting the similarities and differences between them. We will also discuss recent advances in super resolution fluorescence imaging which have elucidated the arrangement of the submembranous axonal cytoskeleton revealing a surprising structural organization necessary to maintain axonal organization and function. Finally, human mutations in axonal domain components have been associated with a growing number of neurological disorders including severe cognitive dysfunction, epilepsy, autism, neurodegenerative diseases and psychiatric disorders. Overall, this review highlights the assembly, maintenance and function of axonal excitable domains, particularly the AIS and nodes of Ranvier, and how abnormalities in these processes may contribute to disease.
PubMed: 28536506
DOI: 10.3389/fncel.2017.00136 -
ELife Jun 2023Neuronal information conductance often involves the transmission of action potentials. The spreading of action potentials along the axonal process of a neuron is based...
Neuronal information conductance often involves the transmission of action potentials. The spreading of action potentials along the axonal process of a neuron is based on three physical parameters: the axial resistance of the axon, the axonal insulation by glial membranes, and the positioning of voltage-gated ion channels. In vertebrates, myelin and channel clustering allow fast saltatory conductance. Here, we show that in voltage-gated sodium and potassium channels, Para and Shal, co-localize and cluster in an area resembling the axon initial segment. The local enrichment of Para but not of Shal localization depends on the presence of peripheral wrapping glial cells. In larvae, relatively low levels of Para channels are needed to allow proper signal transduction and nerves are simply wrapped by glial cells. In adults, the concentration of Para increases and is prominently found at the axon initial segment of motor neurons. Concomitantly, these axon domains are covered by a mesh of glial processes forming a lacunar structure that possibly serves as an ion reservoir. Directly flanking this domain glial processes forming the lacunar area appear to collapse and closely apposed stacks of glial cell processes can be detected, resembling a myelin-like insulation. Thus, development may reflect the evolution of myelin which forms in response to increased levels of clustered voltage-gated ion channels.
Topics: Animals; Myelin Sheath; Drosophila; Drosophila melanogaster; Axons; Neuroglia; Potassium Channels; Motor Neurons; Cluster Analysis
PubMed: 37278291
DOI: 10.7554/eLife.85752 -
Progress in Neurobiology Dec 2023Axo-axonic cells (AACs) provide specialized inhibition to the axon initial segment (AIS) of excitatory neurons and can regulate network output and synchrony. Although...
Axo-axonic cells (AACs) provide specialized inhibition to the axon initial segment (AIS) of excitatory neurons and can regulate network output and synchrony. Although hippocampal dentate AACs are structurally altered in epilepsy, physiological analyses of dentate AACs are lacking. We demonstrate that parvalbumin neurons in the dentate molecular layer express PTHLH, an AAC marker, and exhibit morphology characteristic of AACs. Dentate AACs show high-frequency, non-adapting firing but lack persistent firing in the absence of input and have higher rheobase than basket cells suggesting that AACs can respond reliably to network activity. Early after pilocarpine-induced status epilepticus (SE), dentate AACs receive fewer spontaneous excitatory and inhibitory synaptic inputs and have significantly lower maximum firing frequency. Paired recordings and spatially localized optogenetic stimulation revealed that SE reduced the amplitude of unitary synaptic inputs from AACs to granule cells without altering reliability, short-term plasticity, or AIS GABA reversal potential. These changes compromised AAC-dependent shunting of granule cell firing in a multicompartmental model. These early post-SE changes in AAC physiology would limit their ability to receive and respond to input, undermining a critical brake on the dentate throughput during epileptogenesis.
Topics: Humans; Reproducibility of Results; Dentate Gyrus; Neurons; Axons; Status Epilepticus
PubMed: 37898313
DOI: 10.1016/j.pneurobio.2023.102542 -
Current Topics in Membranes 2016The axon initial segment is a highly specialized neuronal compartment, identified almost 50years ago by the pioneers of electron microscopy. Located in the first 50μm... (Review)
Review
The axon initial segment is a highly specialized neuronal compartment, identified almost 50years ago by the pioneers of electron microscopy. Located in the first 50μm of the axon, it contains unique cytoskeletal features and concentrates a repertoire of specific scaffold and membrane proteins that assembles just after axon determination. The axon initial segment (AIS) supports two crucial physiological functions of the mature neuron: first, it generates and shapes the action potential. Second, it separates the cell body from the axon, preserving the molecular identity of each compartment. In addition to a diffusion barrier restricting membrane proteins and lipids exchange, an intracellular filter has been proposed that could selectively exclude somatodendritic vesicles and recruit axonal cargoes. Finally, the AIS scaffold is capable of morphological plasticity during development or in response to network activity. These changes directly impact the neuron excitability, allowing an adaptive and homeostatic response. These plastic electrogenic properties, as well as the regulation of protein transport to and from the axon, may have important implications in several neuropathological contexts where the AIS structure is altered. Fifty years after its first characterization, the AIS thus emerges as a nexus for both neuronal organization and physiology.
Topics: Animals; Axons; Disease; Electrophysiological Phenomena; Humans; Microscopy, Electron
PubMed: 26781833
DOI: 10.1016/bs.ctm.2015.10.005 -
Cells Aug 2021The 20-60 μm axon initial segment (AIS) is proximally located at the interface between the axon and cell body. AIS has characteristic molecular and structural... (Review)
Review
The 20-60 μm axon initial segment (AIS) is proximally located at the interface between the axon and cell body. AIS has characteristic molecular and structural properties regulated by the crucial protein, ankyrin-G. The AIS contains a high density of Na channels relative to the cell body, which allows low thresholds for the initiation of action potential (AP). Molecular and physiological studies have shown that the AIS is also a key domain for the control of neuronal excitability by homeostatic mechanisms. The AIS has high plasticity in normal developmental processes and pathological activities, such as injury, neurodegeneration, and neurodevelopmental disorders (NDDs). In the first half of this review, we provide an overview of the molecular, structural, and ion-channel characteristics of AIS, AIS regulation through axo-axonic synapses, and axo-glial interactions. In the second half, to understand the relationship between NDDs and AIS, we discuss the activity-dependent plasticity of AIS, the human mutation of AIS regulatory genes, and the pathophysiological role of an abnormal AIS in NDD model animals and patients. We propose that the AIS may provide a potentially valuable structural biomarker in response to abnormal network activity in vivo as well as a new treatment concept at the neural circuit level.
Topics: Action Potentials; Ankyrins; Axon Initial Segment; Humans; Ion Channels; Mutation; Neurodevelopmental Disorders; Neuroglia; Neuronal Plasticity; Spectrin; Synapses
PubMed: 34440880
DOI: 10.3390/cells10082110 -
Nature Neuroscience Aug 2023Genetically defined subgroups of inhibitory interneurons are thought to play distinct roles in learning, but heterogeneity within these subgroups has limited our...
Genetically defined subgroups of inhibitory interneurons are thought to play distinct roles in learning, but heterogeneity within these subgroups has limited our understanding of the scope and nature of their specific contributions. Here we reveal that the chandelier cell (ChC), an interneuron type that specializes in inhibiting the axon-initial segment (AIS) of pyramidal neurons, establishes cortical microcircuits for organizing neural coding through selective axo-axonic synaptic plasticity. We found that organized motor control is mediated by enhanced population coding of direction-tuned premotor neurons, with tuning refined through suppression of irrelevant neuronal activity. ChCs contribute to learning-dependent refinements by providing selective inhibitory control over individual pyramidal neurons rather than global suppression. Quantitative analysis of structural plasticity across axo-axonic synapses revealed that ChCs redistributed inhibitory weights to individual pyramidal neurons during learning. These results demonstrate an adaptive logic of the inhibitory circuit motif responsible for organizing distributed neural representations. Thus, ChCs permit efficient cortical computation in a targeted cell-specific manner.
Topics: Behavior Control; Axons; Neurons; Pyramidal Cells; Synapses; Interneurons
PubMed: 37474640
DOI: 10.1038/s41593-023-01380-x -
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 -
Handbook of Clinical Neurology 2016Ion channels and receptors are the fundamental basis for neuronal communication in the nervous system and are important targets of autoimmunity. The different neuronal... (Review)
Review
Ion channels and receptors are the fundamental basis for neuronal communication in the nervous system and are important targets of autoimmunity. The different neuronal domains contain a unique repertoire of voltage-gated Na(+) (Nav), Ca(2+) (Cav), and K(+) (Kv), as well as other K(+) channels and hyperpolarization-gated cyclic nucleotide-regulated channels. The distinct ion channel distribution defines the electrophysiologic properties of different subtypes of neurons. The different neuronal compartments also express neurotransmitter-gated ion channels, or ionotropic receptors, as well as G protein-coupled receptors. Of particular relevance in the central nervous system are excitatory glutamate receptors and inhibitory γ-aminobutyric acid and glycine receptors. The interactions among different ion channels and receptors regulate neuronal excitability; frequency and pattern of firing of action potentials (AP); propagation of the AP along the axon; neurotransmitter release at synaptic terminals; AP backpropagation from the axon initial segment to the somatodendritic domain; dendritic integration of synaptic signals; and use-dependent plasticity.
Topics: Action Potentials; Animals; Autoimmunity; Central Nervous System; Humans; Ion Channels; Neurons; Neurotransmitter Agents; Signal Transduction
PubMed: 27112669
DOI: 10.1016/B978-0-444-63432-0.00002-5