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Advances in Neurobiology 2023The mature nervous system relies on the polarized morphology of neurons for a directed flow of information. These highly polarized cells use their somatodendritic domain...
The mature nervous system relies on the polarized morphology of neurons for a directed flow of information. These highly polarized cells use their somatodendritic domain to receive and integrate input signals while the axon is responsible for the propagation and transmission of the output signal. However, the axon must perform different functions throughout development before being fully functional for the transmission of information in the form of electrical signals. During the development of the nervous system, axons perform environmental sensing functions, which allow them to navigate through other regions until a final target is reached. Some axons must also establish a regulated contact with other cells before reaching maturity, such as with myelinating glial cells in the case of myelinated axons. Mature axons must then acquire the structural and functional characteristics that allow them to perform their role as part of the information processing and transmitting unit that is the neuron. Finally, in the event of an injury to the nervous system, damaged axons must try to reacquire some of their immature characteristics in a regeneration attempt, which is mostly successful in the PNS but fails in the CNS. Throughout all these steps, glycans perform functions of the outermost importance. Glycans expressed by the axon, as well as by their surrounding environment and contacting cells, encode key information, which is fine-tuned by glycan modifying enzymes and decoded by glycan binding proteins so that the development, guidance, myelination, and electrical transmission functions can be reliably performed. In this chapter, we will provide illustrative examples of how glycans and their binding/transforming proteins code and decode instructive information necessary for fundamental processes in axon physiology.
Topics: Humans; Axons; Neurons; Neuroglia; Polysaccharides
PubMed: 36255676
DOI: 10.1007/978-3-031-12390-0_7 -
Neuron Jan 2012The axon initial segment (AIS) is a specialized membrane region in the axon of neurons where action potentials are initiated. Crucial to the function of the AIS is the... (Review)
Review
The axon initial segment (AIS) is a specialized membrane region in the axon of neurons where action potentials are initiated. Crucial to the function of the AIS is the presence of specific voltage-gated channels clustered at high densities, giving the AIS unique electrical properties. Here we review recent data on the physiology of the AIS. These data indicate that the role of the AIS is far richer than originally thought, leading to the idea that it represents a dynamic signal processing unit within neurons, regulating the integration of synaptic inputs, intrinsic excitability, and transmitter release. Furthermore, these observations point to a critical role of the AIS in disease.
Topics: Action Potentials; Animals; Axons; Humans; Neurons; Sodium Channels
PubMed: 22284179
DOI: 10.1016/j.neuron.2012.01.007 -
Nature Reviews. Neuroscience Aug 2010Ion channel clustering at the axon initial segment (AIS) and nodes of Ranvier has been suggested to be a key evolutionary innovation that enabled the development of the... (Review)
Review
Ion channel clustering at the axon initial segment (AIS) and nodes of Ranvier has been suggested to be a key evolutionary innovation that enabled the development of the complex vertebrate nervous system. This innovation epitomizes a signature feature of neurons, namely polarity. The mechanisms that establish neuronal polarity, channel clustering and axon-dendrite identity during development are becoming clearer. However, much less is known about how polarity is maintained throughout life. Here, I review the role of the AIS in the development and maintenance of neuronal polarity and discuss how disrupted polarity may be a common component of many diseases and injuries that affect the nervous system.
Topics: Animals; Axons; Cell Polarity; Humans; Nervous System Diseases; Neurons
PubMed: 20631711
DOI: 10.1038/nrn2852 -
Scientific Reports May 2022The axon initial segment (AIS) is a region of the neuron that is critical for action potential generation as well as for the regulation of neural activity. This...
The axon initial segment (AIS) is a region of the neuron that is critical for action potential generation as well as for the regulation of neural activity. This specialized structure-characterized by the expression of different types of ion channels as well as adhesion, scaffolding and cytoskeleton proteins-is subjected to morpho-functional plastic changes in length and position upon variations in neural activity or in pathological conditions. In the present study, using immunocytochemistry with the AT8 antibody (phospho-tau S202/T205) and 3D confocal microscopy reconstruction techniques in brain tissue from Alzheimer's disease patients, we found that around half of the cortical pyramidal neurons with hyperphosphorylated tau showed changes in AIS length and position in comparison with AT8-negative neurons from the same cortical layers. We observed a wide variety of AIS alterations in neurons with hyperphosphorylated tau, although the most common changes were a proximal shift or a lengthening of the AISs. Similar results were found in neocortical tissue from non-demented cases with neurons containing hyperphosphorylated tau. These findings support the notion that the accumulation of phospho-tau is associated with structural alterations of the AIS that are likely to have an impact on normal neuronal activity, which might contribute to neuronal dysfunction in AD.
Topics: Alzheimer Disease; Axon Initial Segment; Humans; Neurons; Pyramidal Cells; tau Proteins
PubMed: 35610289
DOI: 10.1038/s41598-022-12700-9 -
Brain Communications 2022Grey matter damage has been established as a key contributor to disability progression in multiple sclerosis. Aside from neuronal loss and axonal transections, which...
Grey matter damage has been established as a key contributor to disability progression in multiple sclerosis. Aside from neuronal loss and axonal transections, which predominate in cortical demyelinated lesions, synaptic alterations have been detected in both demyelinated plaques and normal-appearing grey matter, resulting in functional neuronal damage. The axon initial segment is a key element of neuronal function, responsible for action potential initiation and maintenance of neuronal polarity. Despite several reports of profound axon initial segment alterations in different pathological models, among which experimental auto-immune encephalomyelitis, whether the axon initial segment is affected in multiple sclerosis is still unknown. Using immunohistochemistry, we analysed axon initial segments from control and multiple sclerosis tissue, focusing on layer 5/6 pyramidal neurons in the neocortex and Purkinje cells in the cerebellum and performed analysis on the parameters known to control neuronal excitability, i.e. axon initial segment length and position. We found that the axon initial segment length was increased only in pyramidal neurons of inactive demyelinated lesions, compared with normal appearing grey matter tissue. In contrast, in both cell types, the axon initial segment position was altered, with an increased soma-axon initial segment gap, in both active and inactive demyelinated lesions. In addition, using a computational model, we show that this increased gap between soma and axon initial segment might increase neuronal excitability. Taken together, these results show, for the first time, changes of axon initial segments in multiple sclerosis, in active as well as inactive grey matter lesions in both neocortex and cerebellum, which might alter neuronal function.
PubMed: 36451656
DOI: 10.1093/braincomms/fcac284 -
The Neuroscientist : a Review Journal... Aug 2017The axon initial segment (AIS) is a key neuronal compartment because it is responsible for action potential initiation. The local density of Na channels, the biophysical... (Review)
Review
The axon initial segment (AIS) is a key neuronal compartment because it is responsible for action potential initiation. The local density of Na channels, the biophysical properties of K channels, as well as the length and diameter of the AIS determine the spiking of neurons. These parameters undergo important modifications during development. The development of the AIS is governed by intrinsic mechanisms. In addition, surrounding neuronal networks modify its maturation. As a result, neurons get tuned to particular physiological functions. Neuronal activity also influences the morphology of the mature AIS. When excitatory neurons are hyperactive, their AIS undergo structural changes that decrease their excitability and thereby maintain the activity within a given range. These slow homeostatic regulatory mechanisms occur on a time scale of hours or days. In contrast, the activation of metabotropic receptors modulates the properties of ion channels expressed at the AIS within seconds and consequently produces fast adjustments of neuronal excitability. Recent results suggest that this plasticity plays important roles in physiological functions as diverse as memory formation, hearing, and motor control.
Topics: Action Potentials; Animals; Axon Initial Segment; Ion Channels; Models, Neurological; Neuronal Plasticity; Neurons
PubMed: 27143656
DOI: 10.1177/1073858416648311 -
Brain : a Journal of Neurology Jun 2022This scientific commentary refers to ‘Sensory neurons have an axon initial segment that initiates spontaneous activity in neuropathic pain’ by Nascimento ....
This scientific commentary refers to ‘Sensory neurons have an axon initial segment that initiates spontaneous activity in neuropathic pain’ by Nascimento . (https://doi.org/10.1093/brain/awac078).
Topics: Axon Initial Segment; Axons; Humans; Neuralgia
PubMed: 35661860
DOI: 10.1093/brain/awac156 -
The European Journal of Neuroscience Nov 2011The axon initial segment (AIS), with its dense clusters of voltage-gated ion channels decorating the axonal membrane, regulates action potential initiation and... (Review)
Review
The axon initial segment (AIS), with its dense clusters of voltage-gated ion channels decorating the axonal membrane, regulates action potential initiation and modulation. The AIS also functions as a barrier to maintain axodendritic polarity, and its precise axonal location contributes to the fine-tuning of neuronal excitability. Therefore, it is not surprising that mutations in AIS-related genes, disruption of the molecular organization of the AIS and altered AIS ion channel expression, function, location and/or density are emerging as key players in neurological disorders. Here, we consider the role of the AIS in nervous system disease and injury.
Topics: Action Potentials; Aging; Animals; Ankyrins; Axons; Cell Polarity; Humans; Ion Channels; Mental Disorders; Nervous System; Nervous System Diseases; Neuronal Plasticity; Neurons
PubMed: 22103418
DOI: 10.1111/j.1460-9568.2011.07875.x -
The Journal of Physiological Sciences :... Mar 2016Rapid action potential propagation along myelinated axons requires voltage-gated Na(+) channel clustering at the axon initial segments (AISs) and nodes of Ranvier. The... (Review)
Review
Rapid action potential propagation along myelinated axons requires voltage-gated Na(+) channel clustering at the axon initial segments (AISs) and nodes of Ranvier. The AIS is intrinsically defined by cytoskeletal proteins expressed in axons, whereas nodes of Ranvier are formed by interaction between neurons and myelinating glia. These axonal domains have long been considered stable structures, but recent studies revealed that they are plastic and contribute to fine adjustment of neuronal activities and circuit function. The AIS changes its distribution and maintains neural circuit activity at a constant level. Morphological changes in myelinated nerve structures presumably modulate the excitability of nodal regions and regulate the timing of activity, thereby optimizing signal processing in a neural circuit. This review highlights recent findings on the structural plasticity of these excitable axonal domains.
Topics: Action Potentials; Animals; Axons; Myelin Sheath; Neuroglia; Neuronal Plasticity
PubMed: 26464228
DOI: 10.1007/s12576-015-0413-4 -
Nature Reviews. Neuroscience May 2020
Topics: Axon Initial Segment; Axons; Synapses
PubMed: 32214234
DOI: 10.1038/s41583-020-0295-1