-
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 -
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 -
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 -
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 -
Journal of Neurology, Neurosurgery, and... Feb 2022To report the expanded neurological presentations and oncological associations of tripartite motif-containing protein 46 (TRIM46)-IgG seropositive patients.
OBJECTIVES
To report the expanded neurological presentations and oncological associations of tripartite motif-containing protein 46 (TRIM46)-IgG seropositive patients.
METHODS
Archived sera/cerebrospinal fluid (CSF) were evaluated by tissue-based immunofluorescence assay to identify patients with identical axon initial segment (AIS)-specific staining pattern. Phage immunoprecipitation sequencing (PhIP-Seq) was used to identify the putative autoantigen.
RESULTS
IgG in serum (17) and/or CSF (16) from 25 patients yielded unique AIS-specific staining on murine central nervous system (CNS) tissue. An autoantibody specific for TRIM46 was identified by PhIP-Seq, and autoantigen specificity was confirmed by transfected COS7 cell-based assay. Clinical information was available for 22 TRIM46-IgG seropositive patients. Fifteen were female (68%). Median age was 67 years (range 25-87). Fifteen (68%) patients presented with subacute cerebellar syndrome (six isolated; nine with CNS accompaniments: encephalopathy (three), brainstem signs (two), myelopathy (two), parkinsonism (one)). Other phenotypes included limbic encephalitis (three), encephalopathy with/without seizures (two), myelopathy (two). Eighteen (82%) had cancer: neuroendocrine carcinomas (9; pancreatic (3), small-cell lung (4), oesophagus (1), endometrium (1)), adenocarcinomas (6; lung (2), ovarian (2), endometrial (1), breast (1)), sarcoma (2) and gastrointestinal tumour (1). Neurological symptoms in three followed immune checkpoint inhibitor (ICI) administration.
CONCLUSIONS
This study supports TRIM46-IgG being a biomarker of paraneoplastic CNS disorders and expands the neurological phenotypes, oncological and ICI-related adverse event associations.
Topics: Adult; Aged; Aged, 80 and over; Autoantibodies; Biomarkers; Female; Humans; Limbic Encephalitis; Male; Middle Aged; Nerve Tissue Proteins; Paraneoplastic Syndromes, Nervous System; Retrospective Studies
PubMed: 34921120
DOI: 10.1136/jnnp-2021-326656 -
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 -
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