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Molecular Neurobiology Dec 2021The axon initial segment (AIS) is essential for maintaining neuronal polarity, modulating protein transport into the axon, and action potential generation. These...
The axon initial segment (AIS) is essential for maintaining neuronal polarity, modulating protein transport into the axon, and action potential generation. These functions are supported by a distinctive actin and microtubule cytoskeleton that controls axonal trafficking and maintains a high density of voltage-gated ion channels linked by scaffold proteins to the AIS cytoskeleton. However, our knowledge of the mechanisms and proteins involved in AIS cytoskeleton regulation to maintain or modulate AIS structure is limited. In this context, formins play a significant role in the modulation of actin and microtubules. We show that pharmacological inhibition of formins modifies AIS actin and microtubule characteristics in cultured hippocampal neurons, reducing F-actin density and decreasing microtubule acetylation. Moreover, formin inhibition diminishes sodium channels, ankyrinG and βIV-spectrin AIS density, and AIS length, in cultured neurons and brain slices, accompanied by decreased neuronal excitability. We show that genetic downregulation of the mDia1 formin by interference RNAs also decreases AIS protein density and shortens AIS length. The ankyrinG decrease and AIS shortening observed in pharmacologically inhibited neurons and neuron-expressing mDia1 shRNAs were impaired by HDAC6 downregulation or EB1-GFP expression, known to increase microtubule acetylation or stability. However, actin stabilization only partially prevented AIS shortening without affecting AIS protein density loss. These results suggest that mDia1 maintain AIS composition and length contributing to the stability of AIS microtubules.
Topics: Animals; Axon Initial Segment; Axons; Cells, Cultured; Cytoskeleton; Formins; Hippocampus; Mice; Microtubules; Neurons
PubMed: 34458961
DOI: 10.1007/s12035-021-02531-6 -
Frontiers in Cellular Neuroscience 2017Actin is a versatile and ubiquitous cytoskeletal protein that plays a major role in both the establishment and the maintenance of neuronal polarity. For a long time, the... (Review)
Review
Actin is a versatile and ubiquitous cytoskeletal protein that plays a major role in both the establishment and the maintenance of neuronal polarity. For a long time, the most prominent roles that were attributed to actin in neurons were the movement of growth cones, polarized cargo sorting at the axon initial segment, and the dynamic plasticity of dendritic spines, since those compartments contain large accumulations of actin filaments (F-actin) that can be readily visualized using electron- and fluorescence microscopy. With the development of super-resolution microscopy in the past few years, previously unknown structures of the actin cytoskeleton have been uncovered: a periodic lattice consisting of actin and spectrin seems to pervade not only the whole axon, but also dendrites and even the necks of dendritic spines. Apart from that striking feature, patches of F-actin and deep actin filament bundles have been described along the lengths of neurites. So far, research has been focused on the specific roles of actin in the axon, while it is becoming more and more apparent that in the dendrite, actin is not only confined to dendritic spines, but serves many additional and important functions. In this review, we focus on recent developments regarding the role of actin in dendrite morphology, the regulation of actin dynamics by internal and external factors, and the role of F-actin in dendritic protein trafficking.
PubMed: 28572759
DOI: 10.3389/fncel.2017.00147 -
The Journal of Neuroscience : the... Feb 2018At the base of axons sits a unique compartment called the axon initial segment (AIS). The AIS generates and shapes the action potential before it is propagated along the... (Review)
Review
At the base of axons sits a unique compartment called the axon initial segment (AIS). The AIS generates and shapes the action potential before it is propagated along the axon. Neuronal excitability thus depends crucially on the AIS composition and position, and these adapt to developmental and physiological conditions. The AIS also demarcates the boundary between the somatodendritic and axonal compartments. Recent studies have brought insights into the molecular architecture of the AIS and how it regulates protein trafficking. This Viewpoints article summarizes current knowledge about the AIS and highlights future challenges in understanding this key actor of neuronal physiology.
Topics: Animals; Axon Initial Segment; Humans
PubMed: 29378864
DOI: 10.1523/JNEUROSCI.1922-17.2018 -
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 -
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 -
The Neuroscientist : a Review Journal... Jun 2015The axon initial segment (AIS) is a specialized axonal compartment that is involved in conversion of synaptic potentials into action potentials. Recent studies revealed... (Review)
Review
The axon initial segment (AIS) is a specialized axonal compartment that is involved in conversion of synaptic potentials into action potentials. Recent studies revealed that structural properties of the AIS, such as length and position relative to the soma, are differentiated in a cell-specific manner and shape signal processing of individual neurons. Moreover, these structural properties are not fixed but vary in response to prolonged changes of neuronal activity, which readjusts action potential threshold and compensates for the changes of activity, indicating that this structural plasticity of the AIS works as a homeostatic mechanism and contributes to maintain neuronal activity. Neuronal activity plays a crucial role in formation, maintenance, and refinement of neural circuits as well as in pathogenesis and/or pathophysiology of diseases. Thus, this plasticity should be a key to understand physiology and pathology of the brain.
Topics: Action Potentials; Animals; Axons; Brain; Homeostasis; Humans; Models, Neurological; Neuronal Plasticity; Neurons
PubMed: 24847046
DOI: 10.1177/1073858414535986 -
Current Opinion in Neurobiology Aug 2021Nerve axons are shaped similar to long electric wires to quickly transmit information from one end of the body to the other. To remain healthy and functional, axons... (Review)
Review
Nerve axons are shaped similar to long electric wires to quickly transmit information from one end of the body to the other. To remain healthy and functional, axons depend on a wide range of cellular cargos to be transported from the neuronal cell body to its distal processes. Because of the extended distance, a sophisticated and well-organized trafficking network is required to move cargos up and down the axon. Besides motor proteins driving cargo transport, recent data revealed that subcellular membrane specializations, including the axon initial segment at the beginning of the axon and the membrane-associated periodic skeleton, which extends throughout the axonal length, are important spatial regulators of cargo traffic. In addition, tubulin modifications and microtubule-associated proteins present along the axonal cytoskeleton have been proposed to bias cargo movements. Here, we discuss the recent advances in understanding these multiple layers of regulatory mechanisms controlling axonal transport.
Topics: Axonal Transport; Axons; Kinesins; Microtubules; Neurons
PubMed: 34171618
DOI: 10.1016/j.conb.2021.03.012 -
Glia Nov 2019The study of structural and functional plasticity in the central nervous system (CNS) to date has focused primarily on that of neurons and synapses. However, more recent... (Review)
Review
The study of structural and functional plasticity in the central nervous system (CNS) to date has focused primarily on that of neurons and synapses. However, more recent studies implicate glial cells as key regulators of neural circuit function. Among these, the myelinating glia of the CNS, oligodendrocytes, have been shown to be responsive to extrinsic signals including neuronal activity, and in turn, tune neurophysiological function. Due to the fact that myelin fundamentally alters the conduction properties of axons, much attention has focused on how dynamic regulation of myelination might represent a form of functional plasticity. Here, we highlight recent research that indicates that it is not only myelin, but essentially all the function-regulating components of the myelinated axon that are responsive to neuronal activity. For example, the axon initial segment, nodes of Ranvier, heminodes, axonal termini, and the morphology of the axon itself all exhibit the potential to respond to neuronal activity, and in so doing might underpin specific functional outputs. We also highlight emerging evidence that the myelin sheath itself has a rich physiology capable of influencing axonal physiology. We suggest that to fully understand nervous system plasticity we need to consider the fact that myelinated axon is an integrated functional unit and adaptations that influence the entire functional unit are likely to underpin modifications to neural circuit function.
Topics: Action Potentials; Animals; Axons; Humans; Myelin Sheath; Neuroglia; Neurons; Oligodendroglia
PubMed: 31233642
DOI: 10.1002/glia.23665 -
Cells Apr 2023Brain channelopathies are a group of neurological disorders that result from genetic mutations affecting ion channels in the brain. Ion channels are specialized proteins... (Review)
Review
Brain channelopathies are a group of neurological disorders that result from genetic mutations affecting ion channels in the brain. Ion channels are specialized proteins that play a crucial role in the electrical activity of nerve cells by controlling the flow of ions such as sodium, potassium, and calcium. When these channels are not functioning properly, they can cause a wide range of neurological symptoms such as seizures, movement disorders, and cognitive impairment. In this context, the axon initial segment (AIS) is the site of action potential initiation in most neurons. This region is characterized by a high density of voltage-gated sodium channels (VGSCs), which are responsible for the rapid depolarization that occurs when the neuron is stimulated. The AIS is also enriched in other ion channels, such as potassium channels, that play a role in shaping the action potential waveform and determining the firing frequency of the neuron. In addition to ion channels, the AIS contains a complex cytoskeletal structure that helps to anchor the channels in place and regulate their function. Therefore, alterations in this complex structure of ion channels, scaffold proteins, and specialized cytoskeleton may also cause brain channelopathies not necessarily associated with ion channel mutations. This review will focus on how the AISs structure, plasticity, and composition alterations may generate changes in action potentials and neuronal dysfunction leading to brain diseases. AIS function alterations may be the consequence of voltage-gated ion channel mutations, but also may be due to ligand-activated channels and receptors and AIS structural and membrane proteins that support the function of voltage-gated ion channels.
Topics: Humans; Axon Initial Segment; Axons; Channelopathies; Ion Channels; Brain; Seizures
PubMed: 37190119
DOI: 10.3390/cells12081210 -
Neuroscience Jan 2018The rodent whisker-to-barrel cortex pathway is a classic model to study the effects of sensory experience and deprivation on neuronal circuit formation, not only during... (Review)
Review
The rodent whisker-to-barrel cortex pathway is a classic model to study the effects of sensory experience and deprivation on neuronal circuit formation, not only during development but also in the adult. Decades of research have produced a vast body of evidence highlighting the fundamental role of neuronal activity (spontaneous and/or sensory-evoked) for circuit formation and function. In this context, it has become clear that neuronal adaptation and plasticity is not just a function of the neonatal brain, but persists into adulthood, especially after experience-driven modulation of network status. Mechanisms for structural remodeling of the somatodendritic or axonal domain include microscale alterations of neurites or synapses. At the same time, functional alterations at the nanoscale such as expression or activation changes of channels and receptors contribute to the modulation of intrinsic excitability or input-output relationships. However, it remains elusive how these forms of structural and functional plasticity come together to shape neuronal network formation and function. While specifically somatodendritic plasticity has been studied in great detail, the role of axonal plasticity, (e.g. at presynaptic boutons, branches or axonal microdomains), is rather poorly understood. Therefore, this review will only briefly highlight somatodendritic plasticity and instead focus on axonal plasticity. We discuss (i) the role of spontaneous and sensory-evoked plasticity during critical periods, (ii) the assembly of axonal presynaptic sites, (iii) axonal plasticity in the mature brain under baseline and sensory manipulation conditions, and finally (iv) plasticity of electrogenic axonal microdomains, namely the axon initial segment, during development and in the mature CNS.
Topics: Animals; Axons; Nerve Net; Neuronal Plasticity; Presynaptic Terminals; Rodentia; Somatosensory Cortex
PubMed: 28739523
DOI: 10.1016/j.neuroscience.2017.07.035