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Journal of Alzheimer's Disease : JAD 2023In Alzheimer's disease (AD) brain, neuronal polarity and synaptic connectivity are compromised. A key structure for regulating polarity and functions of neurons is the...
BACKGROUND
In Alzheimer's disease (AD) brain, neuronal polarity and synaptic connectivity are compromised. A key structure for regulating polarity and functions of neurons is the axon initial segment (AIS), which segregates somatodendritic from axonal proteins and initiates action potentials. Toxic tau species, including extracellular oligomers (xcTauOs), spread tau pathology from neuron to neuron by a prion-like process, but few other cell biological effects of xcTauOs have been described.
OBJECTIVE
Test the hypothesis that AIS structure is sensitive to xcTauOs.
METHODS
Cultured wild type (WT) and tau knockout (KO) mouse cortical neurons were exposed to xcTauOs, and quantitative western blotting and immunofluorescence microscopy with anti-TRIM46 monitored effects on the AIS. The same methods were used to compare TRIM46 and two other resident AIS proteins in human hippocampal tissue obtained from AD and age-matched non-AD donors.
RESULTS
Without affecting total TRIM46 levels, xcTauOs reduce the concentration of TRIM46 within the AIS and cause AIS shortening in cultured WT, but not TKO neurons. Lentiviral-driven tau expression in tau KO neurons rescues AIS length sensitivity to xcTauOs. In human AD hippocampus, the overall protein levels of multiple resident AIS proteins are unchanged compared to non-AD brain, but TRIM46 concentration within the AIS and AIS length are reduced in neurons containing neurofibrillary tangles.
CONCLUSION
xcTauOs cause partial AIS damage in cultured neurons by a mechanism dependent on intracellular tau, thereby raising the possibility that the observed AIS reduction in AD neurons in vivo is caused by xcTauOs working in concert with endogenous neuronal tau.
Topics: Mice; Animals; Humans; Axon Initial Segment; Axons; Neurons; Alzheimer Disease; Hippocampus; Mice, Knockout; tau Proteins
PubMed: 37182881
DOI: 10.3233/JAD-221284 -
Brain Sciences Nov 2023Diffuse axonal injury (DAI) is a significant feature of traumatic brain injury (TBI) across all injury severities and is driven by the primary mechanical insult and... (Review)
Review
Diffuse axonal injury (DAI) is a significant feature of traumatic brain injury (TBI) across all injury severities and is driven by the primary mechanical insult and secondary biochemical injury phases. Axons comprise an outer cell membrane, the axolemma which is anchored to the cytoskeletal network with spectrin tetramers and actin rings. Neurofilaments act as space-filling structural polymers that surround the central core of microtubules, which facilitate axonal transport. TBI has differential effects on these cytoskeletal components, with axons in the same white matter tract showing a range of different cytoskeletal and axolemma alterations with different patterns of temporal evolution. These require different antibodies for detection in post-mortem tissue. Here, a comprehensive discussion of the evolution of axonal injury within different cytoskeletal elements is provided, alongside the most appropriate methods of detection and their temporal profiles. Accumulation of amyloid precursor protein (APP) as a result of disruption of axonal transport due to microtubule failure remains the most sensitive marker of axonal injury, both acutely and chronically. However, a subset of injured axons demonstrate different pathology, which cannot be detected via APP immunoreactivity, including degradation of spectrin and alterations in neurofilaments. Furthermore, recent work has highlighted the node of Ranvier and the axon initial segment as particularly vulnerable sites to axonal injury, with loss of sodium channels persisting beyond the acute phase post-injury in axons without APP pathology. Given the heterogenous response of axons to TBI, further characterization is required in the chronic phase to understand how axonal injury evolves temporally, which may help inform pharmacological interventions.
PubMed: 38002566
DOI: 10.3390/brainsci13111607 -
Cellular and Molecular Life Sciences :... Jul 2021The identification of the membrane periodic skeleton (MPS), composed of a periodic lattice of actin rings interconnected by spectrin tetramers, was enabled by the... (Review)
Review
The identification of the membrane periodic skeleton (MPS), composed of a periodic lattice of actin rings interconnected by spectrin tetramers, was enabled by the development of super-resolution microscopy, and brought a new exciting perspective to our view of neuronal biology. This exquisite cytoskeleton arrangement plays an important role on mechanisms regulating neuronal (dys)function. The MPS was initially thought to provide mainly for axonal mechanical stability. Since its discovery, the importance of the MPS in multiple aspects of neuronal biology has, however, emerged. These comprise its capacity to act as a signaling platform, regulate axon diameter-with important consequences on the efficiency of axonal transport and electrophysiological properties- participate in the assembly and function of the axon initial segment, and control axon microtubule stability. Recently, MPS disassembly has also surfaced as an early player in the course of axon degeneration. Here, we will discuss the current knowledge on the role of the MPS in axonal physiology and disease.
Topics: Animals; Axonal Transport; Axons; Cell Membrane; Cytoskeleton; Humans; Spectrin
PubMed: 34085116
DOI: 10.1007/s00018-021-03867-x -
Current Opinion in Neurobiology Aug 2014The axon initial segment (AIS) is a structurally and molecularly unique neuronal compartment of the proximal axon that functions as both a physiological and physical... (Review)
Review
The axon initial segment (AIS) is a structurally and molecularly unique neuronal compartment of the proximal axon that functions as both a physiological and physical bridge between the somatodendritic and axonal domains. The AIS has two main functions: to initiate action potentials and to maintain neuronal polarity. The cytoskeletal scaffold ankyrinG is responsible for these functions and clusters ion channels at the AIS. Recent studies reveal how the AIS forms and remarkable diversity in its structure, function, and composition that may be modulated by neuronal activity and posttranslational modifications of AIS proteins. Furthermore, AIS proteins have been implicated in a variety of human diseases. Here, we discuss these findings and what they teach us about the dynamic AIS.
Topics: Animals; Ankyrins; Axons; Cell Polarity; Cytoskeleton; Humans; Neurons; Nonlinear Dynamics
PubMed: 24705243
DOI: 10.1016/j.conb.2014.03.004 -
Nature Communications Oct 2023Axon initial segment (AIS) cell surface proteins mediate key biological processes in neurons including action potential initiation and axo-axonic synapse formation....
Axon initial segment (AIS) cell surface proteins mediate key biological processes in neurons including action potential initiation and axo-axonic synapse formation. However, few AIS cell surface proteins have been identified. Here, we use antibody-directed proximity biotinylation to define the cell surface proteins in close proximity to the AIS cell adhesion molecule Neurofascin. To determine the distributions of the identified proteins, we use CRISPR-mediated genome editing for insertion of epitope tags in the endogenous proteins. We identify Contactin-1 (Cntn1) as an AIS cell surface protein. Cntn1 is enriched at the AIS through interactions with Neurofascin and NrCAM. We further show that Cntn1 contributes to assembly of the AIS extracellular matrix, and regulates AIS axo-axonic innervation by inhibitory basket cells in the cerebellum and inhibitory chandelier cells in the cortex.
Topics: Axon Initial Segment; Contactin 1; Biotinylation; Synapses; Axons; Membrane Proteins; Antibodies; Biological Phenomena
PubMed: 37884508
DOI: 10.1038/s41467-023-42273-8 -
Frontiers in Cellular Neuroscience 2019Spectrin cytoskeletons are found in all metazoan cells, and their physical interactions between actin and ankyrins establish a meshwork that provides cellular structural... (Review)
Review
Spectrin cytoskeletons are found in all metazoan cells, and their physical interactions between actin and ankyrins establish a meshwork that provides cellular structural integrity. With advanced super-resolution microscopy, the intricate spatial organization and associated functional properties of these cytoskeletons can now be analyzed with unprecedented clarity. Long neuronal processes like peripheral sensory and motor axons may be subject to intense mechanical forces including bending, stretching, and torsion. The spectrin-based cytoskeleton is essential to protect axons against these mechanical stresses. Additionally, spectrins are critical for the assembly and maintenance of axonal excitable domains including the axon initial segment and the nodes of Ranvier (NoR). These sites facilitate rapid and efficient action potential initiation and propagation in the nervous system. Recent studies revealed that pathogenic spectrin variants and diseases that protealyze and breakdown spectrins are associated with congenital neurological disorders and nervous system injury. Here, we review recent studies of spectrins in the nervous system and focus on their functions in axonal health and disease.
PubMed: 31191255
DOI: 10.3389/fncel.2019.00234 -
Science Advances Sep 2023Activity-dependent plasticity of the axon initial segment (AIS) endows neurons with the ability to adapt action potential output to changes in network activity. Action...
Activity-dependent plasticity of the axon initial segment (AIS) endows neurons with the ability to adapt action potential output to changes in network activity. Action potential initiation at the AIS highly depends on the clustering of voltage-gated sodium channels, but the molecular mechanisms regulating their plasticity remain largely unknown. Here, we developed genetic tools to label endogenous sodium channels and their scaffolding protein, to reveal their nanoscale organization and longitudinally image AIS plasticity in hippocampal neurons in slices and primary cultures. We find that -methyl-d-aspartate receptor activation causes both long-term synaptic depression and rapid internalization of AIS sodium channels within minutes. The clathrin-mediated endocytosis of sodium channels at the distal AIS increases the threshold for action potential generation. These data reveal a fundamental mechanism for rapid activity-dependent AIS reorganization and suggests that plasticity of intrinsic excitability shares conserved features with synaptic plasticity.
Topics: Axon Initial Segment; Sodium Channels; Action Potentials; Cluster Analysis; Endocytosis
PubMed: 37713493
DOI: 10.1126/sciadv.adf3885 -
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 -
Danish Medical Journal Feb 2016Serotonin is a major neuromodulator in the central nervous system involved in most physiological functions including appetite regulation, sexual arousal, sleep... (Review)
Review
Serotonin is a major neuromodulator in the central nervous system involved in most physiological functions including appetite regulation, sexual arousal, sleep regulation and motor control. The activity of neurons from the raphe spinal tract, which release serotonin on motoneurons, is positively correlated with motor behaviour. During moderate physical activity, serotonin is released from synaptic terminals onto the dendrites and cell bodies of motoneurons. Serotonin increases the excitability of motoneurons and thereby facilitate muscle contraction by acting on several parallel intracellular pathways. By activating 5-HT1A receptors, serotonin inhibits TWIK-related acid-sensitive potassium channels and small conductance calcium-activated potassium channels. In parallel, serotonin binds to 5-HT2 receptors, which promotes the low-threshold L-type Ca(2+) channels. During intense physical activity, more serotonin is released. The reuptake systems saturate and serotonin spills over to reach extrasynaptic 5-HT1A receptors located on the axon initial segment of motoneurons. This in turn induces the inhibition of the Na(+) channels responsible for the initiation of action potentials. Fewer nerve impulses are generated and muscle contraction becomes weaker. By decreasing the gain of motoneurons, serotonin triggers central fatigue.
Topics: Action Potentials; Animals; Anura; Motor Neurons; Serotonin; Serotonin Receptor Agonists; Spinal Cord; Synaptic Transmission; Turtles
PubMed: 26836802
DOI: No ID Found -
Life (Basel, Switzerland) Dec 2020The precise axonal distribution of specific potassium channels is known to secure the shape and frequency of action potentials in myelinated fibers. The low-threshold... (Review)
Review
The precise axonal distribution of specific potassium channels is known to secure the shape and frequency of action potentials in myelinated fibers. The low-threshold voltage-gated Kv1 channels located at the axon initial segment have a significant influence on spike initiation and waveform. Their role remains partially understood at the juxtaparanodes where they are trapped under the compact myelin bordering the nodes of Ranvier in physiological conditions. However, the exposure of Kv1 channels in de- or dys-myelinating neuropathy results in alteration of saltatory conduction. Moreover, cell adhesion molecules associated with the Kv1 complex, including Caspr2, Contactin2, and LGI1, are target antigens in autoimmune diseases associated with hyperexcitability such as encephalitis, neuromyotonia, or neuropathic pain. The clustering of Kv1.1/Kv1.2 channels at the axon initial segment and juxtaparanodes is based on interactions with cell adhesion molecules and cytoskeletal linkers. This review will focus on the trafficking and assembly of the axonal Kv1 complex in the peripheral and central nervous system (PNS and CNS), during development, and in health and disease.
PubMed: 33374190
DOI: 10.3390/life11010008