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Current Opinion in Neurobiology Aug 2018The axon initial segment (AIS) is a unique domain of the proximal axon serving critical electrical and structural roles including the initiation of action potentials and... (Review)
Review
The axon initial segment (AIS) is a unique domain of the proximal axon serving critical electrical and structural roles including the initiation of action potentials and maintenance of cellular polarity. Recent experimental and theoretical advances demonstrate that the anatomical site for initiation is remarkably diverse. The AIS location varies not only axially, along the axon, but axons also emerge variably from either the soma or proximal dendrites. Here, we review the evidence that the diversity of AIS and axon location has a substantial impact on the electrical properties and speculate that the anatomical heterogeneity of axon locations expands synaptic integration within cell types and improves information processing in neural circuits.
Topics: Animals; Axon Initial Segment; Axons; Cell Polarity; Membrane Potentials; Neurons; Synapses
PubMed: 29533849
DOI: 10.1016/j.conb.2018.02.016 -
Cell Reports Dec 2023Dysregulated neuronal excitability is a hallmark of amyotrophic lateral sclerosis (ALS). We sought to investigate how functional changes to the axon initial segment...
Dysregulated neuronal excitability is a hallmark of amyotrophic lateral sclerosis (ALS). We sought to investigate how functional changes to the axon initial segment (AIS), the site of action potential generation, could impact neuronal excitability in ALS human induced pluripotent stem cell (hiPSC) motor neurons. We find that early TDP-43 and C9orf72 hiPSC motor neurons show an increase in the length of the AIS and impaired activity-dependent AIS plasticity that is linked to abnormal homeostatic regulation of neuronal activity and intrinsic hyperexcitability. In turn, these hyperactive neurons drive increased spontaneous myofiber contractions of in vitro hiPSC motor units. In contrast, late hiPSC and postmortem ALS motor neurons show AIS shortening, and hiPSC motor neurons progress to hypoexcitability. At a molecular level, aberrant expression of the AIS master scaffolding protein ankyrin-G and AIS-specific voltage-gated sodium channels mirror these dynamic changes in AIS function and excitability. Our results point toward the AIS as an important site of dysfunction in ALS motor neurons.
Topics: Humans; Axon Initial Segment; Amyotrophic Lateral Sclerosis; Induced Pluripotent Stem Cells; Motor Neurons; Action Potentials
PubMed: 38019651
DOI: 10.1016/j.celrep.2023.113509 -
The Journal of Experimental Biology Feb 2015Polarized distribution of signaling molecules to axons and dendrites facilitates directional information flow in complex vertebrate nervous systems. The topic we address... (Review)
Review
Polarized distribution of signaling molecules to axons and dendrites facilitates directional information flow in complex vertebrate nervous systems. The topic we address here is when the key aspects of neuronal polarity evolved. All neurons have a central cell body with thin processes that extend from it to cover long distances, and they also all rely on voltage-gated ion channels to propagate signals along their length. The most familiar neurons, those in vertebrates, have additional cellular features that allow them to send directional signals efficiently. In these neurons, dendrites typically receive signals and axons send signals. It has been suggested that many of the distinct features of axons and dendrites, including the axon initial segment, are found only in vertebrates. However, it is now becoming clear that two key cytoskeletal features that underlie polarized sorting, a specialized region at the base of the axon and polarized microtubules, are found in invertebrate neurons as well. It thus seems likely that all bilaterians generate axons and dendrites in the same way. As a next step, it will be extremely interesting to determine whether the nerve nets of cnidarians and ctenophores also contain polarized neurons with true axons and dendrites, or whether polarity evolved in concert with the more centralized nervous systems found in bilaterians.
Topics: Animals; Axons; Biological Evolution; Cytoskeleton; Dendrites; Invertebrates; Microtubules; Neurons
PubMed: 25696820
DOI: 10.1242/jeb.112359 -
Advances in Experimental Medicine and... 2019Propagation of action potentials along axons is optimized through interactions between neurons and myelinating glial cells. Myelination drives division of the axons into... (Review)
Review
Propagation of action potentials along axons is optimized through interactions between neurons and myelinating glial cells. Myelination drives division of the axons into distinct molecular domains including nodes of Ranvier. The high density of voltage-gated sodium channels at nodes generates action potentials allowing for rapid and efficient saltatory nerve conduction. At paranodes flanking both sides of the nodes, myelinating glial cells interact with axons, forming junctions that are essential for node formation and maintenance. Recent studies indicate that the disruption of these specialized axonal domains is involved in the pathophysiology of various neurological diseases. Loss of paranodal axoglial junctions due to genetic mutations or autoimmune attack against the paranodal proteins leads to nerve conduction failure and neurological symptoms. Breakdown of nodal and paranodal proteins by calpains, the calcium-dependent cysteine proteases, may be a common mechanism involved in various nervous system diseases and injuries. This chapter reviews recent progress in neurobiology and pathophysiology of specialized axonal domains along myelinated nerve fibers.
Topics: Axons; Humans; Nerve Fibers, Myelinated; Neural Conduction; Neuroglia
PubMed: 31760639
DOI: 10.1007/978-981-32-9636-7_6 -
Frontiers in Cellular Neuroscience 2016Neurons are highly polarized cells exhibiting axonal and somatodendritic domains with distinct complements of cytoplasmic organelles. Although some organelles are widely... (Review)
Review
Neurons are highly polarized cells exhibiting axonal and somatodendritic domains with distinct complements of cytoplasmic organelles. Although some organelles are widely distributed throughout the neuronal cytoplasm, others are segregated to either the axonal or somatodendritic domains. Recent findings show that organelle segregation is largely established at a pre-axonal exclusion zone (PAEZ) within the axon hillock. Polarized sorting of cytoplasmic organelles at the PAEZ is proposed to depend mainly on their selective association with different microtubule motors and, in turn, with distinct microtubule arrays. Somatodendritic organelles that escape sorting at the PAEZ can be subsequently retrieved at the axon initial segment (AIS) by a microtubule- and/or actin-based mechanism. Dynamic sorting along the PAEZ-AIS continuum can thus explain the polarized distribution of cytoplasmic organelles between the axonal and somatodendritic domains.
PubMed: 27065809
DOI: 10.3389/fncel.2016.00088 -
Experimental & Molecular Medicine Jul 2022Ankyrin proteins act as molecular scaffolds and play an essential role in regulating cellular functions. Recent evidence has implicated the ANK3 gene, encoding... (Review)
Review
Ankyrin proteins act as molecular scaffolds and play an essential role in regulating cellular functions. Recent evidence has implicated the ANK3 gene, encoding ankyrin-G, in bipolar disorder (BD), schizophrenia (SZ), and autism spectrum disorder (ASD). Within neurons, ankyrin-G plays an important role in localizing proteins to the axon initial segment and nodes of Ranvier or to the dendritic shaft and spines. In this review, we describe the expression patterns of ankyrin-G isoforms, which vary according to the stage of brain development, and consider their functional differences. Furthermore, we discuss how posttranslational modifications of ankyrin-G affect its protein expression, interactions, and subcellular localization. Understanding these mechanisms leads us to elucidate potential pathways of pathogenesis in neurodevelopmental and psychiatric disorders, including BD, SZ, and ASD, which are caused by rare pathogenic mutations or changes in the expression levels of ankyrin-G in the brain.
Topics: Ankyrins; Autism Spectrum Disorder; Bipolar Disorder; Brain; Humans; Neurons
PubMed: 35794211
DOI: 10.1038/s12276-022-00798-w -
Molecular and Cellular Neurosciences Sep 2018Ankyrins are broadly expressed adaptors that organize diverse membrane proteins into specialized domains and link them to the sub-membranous cytoskeleton. In neurons,... (Review)
Review
Ankyrins are broadly expressed adaptors that organize diverse membrane proteins into specialized domains and link them to the sub-membranous cytoskeleton. In neurons, ankyrins are known to have essential roles in organizing the axon initial segment and nodes of Ranvier. However, recent studies have revealed novel functions for ankyrins at synapses, where they organize and stabilize neurotransmitter receptors, modulate dendritic spine morphology and control adhesion to the presynaptic site. Ankyrin genes have also been highly associated with a range of neurodevelopmental and psychiatric diseases, including bipolar disorder, schizophrenia and autism, which all demonstrate overlap in their genetics, mechanisms and phenotypes. This review discusses the novel synaptic functions of ankyrin proteins in neurons, and places these exciting findings in the context of ANK genes as key neuropsychiatric disorder risk-factors.
Topics: Animals; Ankyrins; Humans; Neurodevelopmental Disorders; Neuronal Plasticity; Synapses
PubMed: 29730177
DOI: 10.1016/j.mcn.2018.04.010 -
The Journal of Neuroscience : the... Sep 2023Neurons are remarkably polarized structures: dendrites spread and branch to receive synaptic inputs while a single axon extends and transmits action potentials (APs) to...
Neurons are remarkably polarized structures: dendrites spread and branch to receive synaptic inputs while a single axon extends and transmits action potentials (APs) to downstream targets. Neuronal polarity is maintained by the axon initial segment (AIS), a region between the soma and axon proper that is also the site of action potential (AP) generation. This polarization between dendrites and axons extends to inhibitory neurotransmission. In adulthood, the neurotransmitter GABA hyperpolarizes dendrites but instead depolarizes axons. These differences in function collide at the AIS. Multiple studies have shown that GABAergic signaling in this region can share properties of either the mature axon or mature dendrite, and that these properties evolve over a protracted period encompassing periadolescent development. Here, we explored how developmental changes in GABAergic signaling affect AP initiation. We show that GABA at the axon initial segment inhibits action potential initiation in layer (L)2/3 pyramidal neurons in prefrontal cortex from mice of either sex across GABA reversal potentials observed in periadolescence. These actions occur largely through current shunts generated by GABA receptors and changes in voltage-gated channel properties that affected the number of channels that could be recruited for AP electrogenesis. These results suggest that GABAergic neurons targeting the axon initial segment provide an inhibitory "veto" across the range of GABA polarity observed in normal adolescent development, regardless of GABAergic synapse reversal potential. GABA receptors are a major class of neurotransmitter receptors in the brain. Typically, GABA receptors inhibit neurons by allowing influx of negatively charged chloride ions into the cell. However, there are cases where local chloride concentrations promote chloride efflux through GABA receptors. Such conditions exist early in development in neocortical pyramidal cell axon initial segments (AISs), where action potentials (APs) initiate. Here, we examined how chloride efflux in early development interacts with mechanisms that support action potential initiation. We find that this efflux, despite moving membrane potential closer to action potential threshold, is nevertheless inhibitory. Thus, GABA at the axon initial segment is likely to be inhibitory for action potential initiation independent of whether chloride flows out or into neurons via these receptors.
Topics: Animals; Mice; Axon Initial Segment; Action Potentials; Chlorides; GABAergic Neurons; Receptors, GABA-A; gamma-Aminobutyric Acid
PubMed: 37596053
DOI: 10.1523/JNEUROSCI.0605-23.2023 -
Current Opinion in Neurobiology Aug 2016Neurons are organized and connected into functional circuits by axons that conduct action potentials. Many vertebrate axons are myelinated and further subdivided into... (Review)
Review
Neurons are organized and connected into functional circuits by axons that conduct action potentials. Many vertebrate axons are myelinated and further subdivided into excitable domains that include the axon initial segment (AIS) and nodes of Ranvier. Nodes of Ranvier regenerate and propagate action potentials, while AIS regulate action potential initiation and neuronal polarity. Two distinct cytoskeletons control axon structure and function: 1) a submembranous ankyrin/spectrin cytoskeleton that clusters ion channels and provides mechanical support, and 2) a microtubule-based cytoskeleton that controls selective trafficking of dendritic and axonal cargoes. Here, we review recent studies that provide significant additional insight into the cytoskeleton-dependent mechanisms controlling the functional organization of axons.
Topics: Animals; Ankyrins; Axons; Cytoskeleton; Neurons; Ranvier's Nodes
PubMed: 27203619
DOI: 10.1016/j.conb.2016.05.001 -
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