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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 -
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 -
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 -
PLoS Computational Biology Jan 2022Populations of cortical neurons respond to common input within a millisecond. Morphological features and active ion channel properties were suggested to contribute to...
Populations of cortical neurons respond to common input within a millisecond. Morphological features and active ion channel properties were suggested to contribute to this astonishing processing speed. Here we report an exhaustive study of ultrafast population coding for varying axon initial segment (AIS) location, soma size, and axonal current properties. In particular, we studied their impact on two experimentally observed features 1) precise action potential timing, manifested in a wide-bandwidth dynamic gain, and 2) high-frequency boost under slowly fluctuating correlated input. While the density of axonal channels and their distance from the soma had a very small impact on bandwidth, it could be moderately improved by increasing soma size. When the voltage sensitivity of axonal currents was increased we observed ultrafast coding and high-frequency boost. We conclude that these computationally relevant features are strongly dependent on axonal ion channels' voltage sensitivity, but not their number or exact location. We point out that ion channel properties, unlike dendrite size, can undergo rapid physiological modification, suggesting that the temporal accuracy of neuronal population encoding could be dynamically regulated. Our results are in line with recent experimental findings in AIS pathologies and establish a framework to study structure-function relations in AIS molecular design.
Topics: Action Potentials; Axons; Computational Biology; Ion Channels; Models, Neurological; Neurons
PubMed: 35041645
DOI: 10.1371/journal.pcbi.1009775 -
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 -
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 -
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