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Cell Jan 2020The propagation of electrical impulses along axons is highly accelerated by the myelin sheath and produces saltating or "jumping" action potentials across internodes,...
The propagation of electrical impulses along axons is highly accelerated by the myelin sheath and produces saltating or "jumping" action potentials across internodes, from one node of Ranvier to the next. The underlying electrical circuit, as well as the existence and role of submyelin conduction in saltatory conduction remain, however, elusive. Here, we made patch-clamp and high-speed voltage-calibrated optical recordings of potentials across the nodal and internodal axolemma of myelinated neocortical pyramidal axons combined with electron microscopy and experimentally constrained cable modeling. Our results reveal a nanoscale yet conductive periaxonal space, incompletely sealed at the paranodes, which separates the potentials across the low-capacitance myelin sheath and internodal axolemma. The emerging double-cable model reproduces the recorded evolution of voltage waveforms across nodes and internodes, including rapid nodal potentials traveling in advance of attenuated waves in the internodal axolemma, revealing a mechanism for saltation across time and space.
Topics: Action Potentials; Animals; Axons; Male; Models, Neurological; Myelin Sheath; Nerve Fibers, Myelinated; Patch-Clamp Techniques; Pyramidal Cells; Ranvier's Nodes; Rats; Rats, Wistar
PubMed: 31883793
DOI: 10.1016/j.cell.2019.11.039 -
Results and Problems in Cell... 2009During evolution, as organisms increased in complexity and function, the need for the ensheathment and insulation of axons by glia became vital for faster conductance of... (Review)
Review
During evolution, as organisms increased in complexity and function, the need for the ensheathment and insulation of axons by glia became vital for faster conductance of action potentials in nerves. Myelination, as the process is termed, facilitates the formation of discrete domains within the axolemma that are enriched in ion channels, and macromolecular complexes consisting of cell adhesion molecules and cytoskeletal regulators. While it is known that glia play a substantial role in the coordination and organization of these domains, the mechanisms involved and signals transduced between the axon and glia, as well as the proteins regulating axo-glial junction formation remain elusive. Emerging evidence has shed light on the processes regulating myelination and domain differentiation, and key molecules have been identified that are required for their assembly and maintenance. This review highlights these recent findings, and relates their significance to domain disorganization as seen in several demyelinating disorders and other neuropathies.
Topics: Animals; Axons; Cell Differentiation; Central Nervous System Diseases; Disease Models, Animal; Humans; Nerve Fibers, Myelinated; Neurons; Ranvier's Nodes
PubMed: 19343313
DOI: 10.1007/400_2009_3 -
Brain Research Reviews Jun 2011Demyelinating diseases are characterized by an extensive loss of oligodendrocytes and myelin sheaths from axolemma. These neurological disorders are a common cause of... (Review)
Review
Demyelinating diseases are characterized by an extensive loss of oligodendrocytes and myelin sheaths from axolemma. These neurological disorders are a common cause of disability in young adults, but so far, there is no effective treatment against them. It has been suggested that neural stem cells (NSCs) may play an important role in brain repair therapies. NSCs in the adult subventricular zone (SVZ), also known as Type-B cells, are multipotential cells that can self-renew and give rise to neurons and glia. Recent findings have shown that cells derived from SVZ Type-B cells actively respond to epidermal-growth-factor (EGF) stimulation becoming highly migratory and proliferative. Interestingly, a subpopulation of these EGF-activated cells expresses markers of oligodendrocyte precursor cells (OPCs). When EGF administration is removed, SVZ-derived OPCs differentiate into myelinating and pre-myelinating oligodendrocytes in the white matter tracts of corpus callosum, fimbria fornix and striatum. In the presence of a demyelinating lesion, OPCs derived from EGF-stimulated SVZ progenitors contribute to myelin repair. Given their high migratory potential and their ability to differentiate into myelin-forming cells, SVZ NSCs represent an important endogenous source of OPCs for preserving the oligodendrocyte population in the white matter and for the repair of demyelinating injuries.
Topics: Animals; Cell Differentiation; Cell Movement; Cell Proliferation; Cerebral Ventricles; Demyelinating Diseases; Epidermal Growth Factor; Humans; Nerve Fibers, Myelinated; Nerve Regeneration; Neural Stem Cells; Oligodendroglia
PubMed: 21236296
DOI: 10.1016/j.brainresrev.2011.01.001 -
Journal of Neuroscience Research May 2013Over a century ago, Ramon y Cajal first proposed the idea of a directionality involved in nerve conduction and neuronal communication. Decades later, it was discovered... (Review)
Review
Over a century ago, Ramon y Cajal first proposed the idea of a directionality involved in nerve conduction and neuronal communication. Decades later, it was discovered that myelin, produced by glial cells, insulated axons with periodic breaks where nodes of Ranvier (nodes) form to allow for saltatory conduction. In the peripheral nervous system (PNS), Schwann cells are the glia that can either individually myelinate the axon from one neuron or ensheath axons of many neurons. In the central nervous system (CNS), oligodendrocytes are the glia that myelinate axons from different neurons. Review of more recent studies revealed that this myelination created polarized domains adjacent to the nodes. However, the molecular mechanisms responsible for the organization of axonal domains are only now beginning to be elucidated. The molecular domains in myelinated axons include the axon initial segment (AIS), where various ion channels are clustered and action potentials are initiated; the node, where sodium channels are clustered and action potentials are propagated; the paranode, where myelin loops contact with the axolemma; the juxtaparanode (JXP), where delayed-rectifier potassium channels are clustered; and the internode, where myelin is compactly wrapped. Each domain contains a unique subset of proteins critical for the domain's function. However, the roles of these proteins in axonal domain organization are not fully understood. In this review, we highlight recent advances on the molecular nature and functions of some of the components of each axonal domain and their roles in axonal domain organization and maintenance for proper neuronal communication.
Topics: Animals; Axonal Transport; Axons; Membrane Lipids; Myelin Proteins; Myelin Sheath; Nervous System; Neuroglia; Neurons; Ranvier's Nodes
PubMed: 23404451
DOI: 10.1002/jnr.23197 -
Journal of Lipid Research Feb 1981The lipid composition was determined for axolemma-enriched fractions and myelin which were isolated via a preparation of purified myelinated axons. The myelin had a...
The lipid composition was determined for axolemma-enriched fractions and myelin which were isolated via a preparation of purified myelinated axons. The myelin had a lipid composition which was compatible with that previously reported for myelin isolated by alternative procedures. The most dense axolemma-enriched fraction contained 25.3% cholesterol, 25.8% galactolipid (21.3% cerebrosides and 4.8% sulfatides), and 48.9% phospholipid. The major phospholipids were the ethanolamine phospholipid (19.8% of total lipid weight; 49.0% in the plasmalogen form) and choline phospholipids (18.7% of total lipid weight; 16.0% in the plasmalogen form) with lesser amounts of sphingomyelin, phosphatidylserine, and phosphatidylinositol also present; the ganglioside content was 13.9 micrograms of acetylneuraminic acid per mg protein. The less dense axolemma-enriched fraction had a lipid composition which was intermediate between that of myelin and the more dense axolemma-enriched fraction. On the average, less than 2.3% of the total protein in the axolemma-enriched fraction was myelin basic protein. Both axolemma-enriched fractions stained uniformly with Luxol fast blue and demonstrated specific saxitoxin-binding which was enriched 2- to 7-fold over that of the whole white matter homogenate from which the fractions were isolated. The choline and ethanolamine phospholipids in that most dense axolemma-enriched fractions contained a greater percentage of unsaturated fatty acids compared with the comparable phospholipids in myelin. The content of unsaturated fatty acids in these phospholipids of the axolemma-enriched fraction was not as great as that of human CNS synaptic plasma membranes. However, the chain length distribution of these phospholipid fatty acids was similar in myelin, synaptic plasma membrane, and the axolemma-enriched fraction. The distribution of aldehydes derived from the ethanolamine phospholipids of the more dense axolemma-enriched fraction closely resemble the distribution of the comparable aldehydes in the myelin fraction. The possible origin and function of the lipids in the axolemma-enriched fractions are discussed.
Topics: Aged; Axons; Brain Chemistry; Fatty Acids; Humans; Membrane Lipids; Middle Aged; Myelin Sheath; Phosphatidylcholines; Phosphatidylethanolamines; Saxitoxin; Subcellular Fractions
PubMed: 7240954
DOI: No ID Found -
Current Opinion in Neurobiology Dec 2013Nodes of Ranvier are specialized axonal domains formed in response to a glial signal. Recent research advances have revealed that both CNS and PNS nodes form by several... (Review)
Review
Nodes of Ranvier are specialized axonal domains formed in response to a glial signal. Recent research advances have revealed that both CNS and PNS nodes form by several overlapping molecular mechanisms. However, the precise nature of these mechanisms and the hierarchy existing between them is considerably different in CNS versus PNS nodes. Namely, the Schwann cells of the PNS, which directly contact the nodal axolemma, secrete proteins that cluster axonodal components at the edges of the growing myelin segment. In contrast, the formation of CNS nodes, which are not contacted by the myelinating glia, is surprisingly similar to the assembly of the axon initial segment and depends largely on axonal diffusion barriers.
Topics: Animals; Humans; Neurogenesis; Neuroglia; Neurons; Ranvier's Nodes
PubMed: 23831261
DOI: 10.1016/j.conb.2013.06.003 -
The Journal of General Physiology Sep 1966The penetration of (14)C-labeled erythritol, mannitol, and sucrose through the axolemma was determined in medium sized paired axons, one at rest and the other stimulated...
The penetration of (14)C-labeled erythritol, mannitol, and sucrose through the axolemma was determined in medium sized paired axons, one at rest and the other stimulated 25 times per sec. The resting permeabilities, in 10(-7) cm/sec, are erythritol, 2.9 +/- 0.3 (mean +/- SEM); mannitol, 2.3 +/- 0.4; and sucrose 0.9 +/- 0.1. In the stimulated axons they are: erythritol, 5.2 +/- 0.3; mannitol, 4.0 +/- 0.5; and sucrose, 1.8 +/- 0.3. Thus, the calculated permeabilities during activity (1 msec per impulse), in the same units, are: 100, 75, and 38, respectively. These changes in permeability are reversible. The effects of external potassium and sodium concentrations on erythritol penetration were also studied. At rest, erythritol penetration is independent of potassium and sodium concentrations. In the stimulated axons, erythritol penetration decreases when the extracellular sodium is diminished. Sodium influx (not the efflux) decreases during rest and activity when the extracellular sodium is diminished. The diminution during activity of erythritol and sodium entries in low sodium solutions may be related to a decrease of a drag effect of sodium ions on the nonelectrolyte molecules or to independent effects of the sodium concentration on sodium influx and the nonelectrolyte pathways. The axolemma discriminates among erythritol, mannitol, sucrose, and the different ionic species during rest and activity.
Topics: Alcohols; Animals; Axons; Carbon Isotopes; Cell Membrane; Cell Membrane Permeability; Erythritol; Mannitol; Mollusca; Neurons; Potassium; Sodium; Sucrose
PubMed: 5971032
DOI: 10.1085/jgp.50.1.43 -
Frontiers in Physiology 2023Neuroscientists and Cell Biologists have known for many decades that eukaryotic cells, including neurons, are surrounded by a plasmalemma/axolemma consisting of a... (Review)
Review
Neuroscientists and Cell Biologists have known for many decades that eukaryotic cells, including neurons, are surrounded by a plasmalemma/axolemma consisting of a phospholipid bilayer that regulates trans-membrane diffusion of ions (including calcium) and other substances. Cells often incur plasmalemmal damage traumatic injury and various diseases. If the damaged plasmalemma is not rapidly repaired within minutes, activation of apoptotic pathways by calcium influx often results in cell death. We review publications reporting what is less-well known (and not yet covered in neuroscience or cell biology textbooks): that calcium influx at the lesion sites ranging from small nm-sized holes to complete axonal transection activates parallel biochemical pathways that induce vesicles/membrane-bound structures to migrate and interact to restore original barrier properties and eventual reestablishment of the plasmalemma. We assess the reliability of, and problems with, various measures (e.g, membrane voltage, input resistance, current flow, tracer dyes, confocal microscopy, transmission and scanning electron microscopy) used individually and in combination to assess plasmalemmal sealing in various cell types (e.g., invertebrate giant axons, oocytes, hippocampal and other mammalian neurons). We identify controversies such as plug patch hypotheses that attempt to account for currently available data on the subcellular mechanisms of plasmalemmal repair/sealing. We describe current research gaps and potential future developments, such as much more extensive correlations of biochemical/biophysical measures with sub-cellular micromorphology. We compare and contrast naturally occurring sealing with recently-discovered artificially-induced plasmalemmal sealing by polyethylene glycol (PEG) that bypasses all natural pathways for membrane repair. We assess other recent developments such as adaptive membrane responses in neighboring cells following injury to an adjacent cell. Finally, we speculate how a better understanding of the mechanisms involved in natural and artificial plasmalemmal sealing is needed to develop better clinical treatments for muscular dystrophies, stroke and other ischemic conditions, and various cancers.
PubMed: 37008019
DOI: 10.3389/fphys.2023.1114779 -
Frontiers in Neurology 2020Traumatic brain injuries are a leading cause of morbidity and mortality worldwide. With almost 50% of traumatic brain injuries being related to axonal damage,...
Traumatic brain injuries are a leading cause of morbidity and mortality worldwide. With almost 50% of traumatic brain injuries being related to axonal damage, understanding the nature of cellular level impairment is crucial. Experimental observations have so far led to the formulation of conflicting theories regarding the cellular primary injury mechanism. Disruption of the axolemma, or alternatively cytoskeletal damage has been suggested mainly as injury trigger. However, mechanoporation thresholds of generic membranes seem not to overlap with the axonal injury deformation range and microtubules appear too stiff and too weakly connected to undergo mechanical breaking. Here, we aim to shed a light on the mechanism of primary axonal injury, bridging finite element and molecular dynamics simulations. Despite the necessary level of approximation, our models can accurately describe the mechanical behavior of the unmyelinated axon and its membrane. More importantly, they give access to quantities that would be inaccessible with an experimental approach. We show that in a typical injury scenario, the axonal cortex sustains deformations large enough to entail pore formation in the adjoining lipid bilayer. The observed axonal deformation of 10-12% agree well with the thresholds proposed in the literature for axonal injury and, above all, allow us to provide quantitative evidences that do not exclude pore formation in the membrane as a result of trauma. Our findings bring to an increased knowledge of axonal injury mechanism that will have positive implications for the prevention and treatment of brain injuries.
PubMed: 32082244
DOI: 10.3389/fneur.2020.00025