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ELife Jun 2022Pyramidal neurons with axons that exit from dendrites rather than the cell body itself are relatively common in non-primates, but rare in monkeys and humans.
Pyramidal neurons with axons that exit from dendrites rather than the cell body itself are relatively common in non-primates, but rare in monkeys and humans.
Topics: Axons; Cell Body; Neurons; Pyramidal Cells
PubMed: 35647816
DOI: 10.7554/eLife.79839 -
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 -
Nature Communications Dec 2023The axon initial segment (AIS) is a specialized neuronal compartment required for action potential generation and neuronal polarity. However, understanding the...
The axon initial segment (AIS) is a specialized neuronal compartment required for action potential generation and neuronal polarity. However, understanding the mechanisms regulating AIS structure and function has been hindered by an incomplete knowledge of its molecular composition. Here, using immuno-proximity biotinylation we further define the AIS proteome and its dynamic changes during neuronal maturation. Among the many AIS proteins identified, we show that SCRIB is highly enriched in the AIS both in vitro and in vivo, and exhibits a periodic architecture like the axonal spectrin-based cytoskeleton. We find that ankyrinG interacts with and recruits SCRIB to the AIS. However, loss of SCRIB has no effect on ankyrinG. This powerful and flexible approach further defines the AIS proteome and provides a rich resource to elucidate the mechanisms regulating AIS structure and function.
Topics: Axon Initial Segment; Proteome; Biotinylation; Axons; Neurons
PubMed: 38081810
DOI: 10.1038/s41467-023-44015-2 -
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 -
Acta Biologica Hungarica 2002The origin of the axon was studied in Golgi-Kopsch impregnated specimens prepared from the spinal cord and brain of adult rats. Five types of neurons were sampled: large...
The origin of the axon was studied in Golgi-Kopsch impregnated specimens prepared from the spinal cord and brain of adult rats. Five types of neurons were sampled: large ventral horn neurons, neurons in the intermediate zone and ventral horn of the spinal cord, antenna-type neurons in the spinal dorsal horn, neurons in the thalamus, and neurons in the hypothalamus. The axon originated from the perikaryon in 76% of the large ventral horn neurons and in 64% of the neurons in the thalamus. In contrast, the axon emerged from one of the dendrites in 75% of the neurons in the intermediate zone and the ventral horn of the spinal cord and in 68% of the neurons in the hypothalamus. In the case of the antenna-type neurons in the spinal dorsal horn, the axon often originated from one of the dendrites, but never from a dorsally oriented dendrite. The mean distance of the axon hillock of dendritic origin was the longest in the neurons in the intermediate zone and the ventral horn of the spinal cord. The size of the axon hillock was proportional to the size of the perikaryon. The impregnated portion of the axon was longest in the large ventral horn neurons.
Topics: Animals; Anterior Horn Cells; Axons; Hypothalamus; Neurons; Posterior Horn Cells; Rats; Staining and Labeling; Thalamus
PubMed: 12064768
DOI: 10.1556/ABiol.53.2002.1-2.15 -
Nature Jan 1996
Topics: Axons; Carbocyanines; Cell Membrane; Dendrites; Diffusion; Fluorescent Dyes; Hippocampus; Lipid Metabolism; Membrane Proteins
PubMed: 8538784
DOI: 10.1038/379213a0 -
Developmental Biology Sep 2022Neurons are highly polarized cells with extensive axonal and dendritic projections that send and receive signals over long distances. Neuronal polarity requires sorting... (Review)
Review
Neurons are highly polarized cells with extensive axonal and dendritic projections that send and receive signals over long distances. Neuronal polarity requires sorting and maintaining a unique set of proteins to the neuron's distinct axonal and somatodendritic domains. The axon initial segment (AIS) is a specialized subcellular region located between these two domains and is critical for neuronal polarity. The AIS has a complex and elaborately organized molecular structure that enables its functions in neuronal polarity. Disruption of the AIS is associated with neurodevelopmental and neuropsychiatric disease pathologies, thus highlighting the importance of the AIS in neuronal physiology. This review discusses recent progress toward understanding the molecular architecture of the AIS and its importance in neuronal polarity through regulating protein diffusion and vesicular trafficking.
Topics: Axon Initial Segment; Axons; Cell Polarity; Neurons; Protein Transport
PubMed: 35640681
DOI: 10.1016/j.ydbio.2022.05.016 -
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 -
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 -
The Journal of Cell Biology Dec 1968The axon of the pyramidal neuron in the cerebral cortex arises either directly from the perikaryon or as a branch from a basal dendrite. When it arises from the...
The axon of the pyramidal neuron in the cerebral cortex arises either directly from the perikaryon or as a branch from a basal dendrite. When it arises from the perikaryon, an axon hillock is present. The hillock is a region in which there is a transition between the cytological features of the perikaryon and those of the initial segment of the axon. Thus, in the hillock there is a diminution in the number of ribosomes and a beginning of the fasciculation of microtubules that characterize the initial segment. Not all of the microtubules entering the hillock from the perikaryon continue into the initial segment. Distally, the axon hillock ends where the dense undercoating of the plasma membrane of the initial segment commences. Dense material also appears in the extracellular space surrounding the initial segment. The initial segment of the pyramidal cell axon contains a cisternal organelle consisting of stacks of flattened cisternae alternating with plates of dense granular material. These cisternal organelles resemble the spine apparatuses that occur in the dendritic spines of this same neuron. Axo-axonal synapses are formed between the initial segment and surrounding axon terminals. The axon terminals contain clear synaptic vesicles and, at the synaptic junctions, both synaptic complexes and puncta adhaerentia are present.
Topics: Animals; Axons; Cerebral Cortex; Dendrites; Microscopy, Electron; Neurons; Rats; Synapses
PubMed: 5699934
DOI: 10.1083/jcb.39.3.604