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Frontiers in Cellular Neuroscience 2023Ever since the work of Edgar Adrian, the neuronal action potential has been considered as an electric signal, modeled and interpreted using concepts and theories lent...
Ever since the work of Edgar Adrian, the neuronal action potential has been considered as an electric signal, modeled and interpreted using concepts and theories lent from electronic engineering. Accordingly, the electric action potential, as the prime manifestation of neuronal excitability, serving processing and reliable "long distance" communication of the information contained in the signal, was defined as a non-linear, self-propagating, regenerative, wave of electrical activity that travels along the surface of nerve cells. Thus, in the ground-breaking theory and mathematical model of Hodgkin and Huxley (HH), linking Nernst's treatment of the electrochemistry of semi-permeable membranes to the physical laws of electricity and Kelvin's cable theory, the electrical characteristics of the action potential are presented as the result of the depolarization-induced, voltage- and time-dependent opening and closure of ion channels in the membrane allowing the passive flow of charge, particularly in the form of Na and K -ions, into and out of the neuronal cytoplasm along the respective electrochemical ion gradient. In the model, which treats the membrane as a capacitor and ion channels as resistors, these changes in ionic conductance across the membrane cause a sudden and transient alteration of the transmembrane potential, i.e., the action potential, which is then carried forward and spreads over long(er) distances by means of both active and passive conduction dependent on local current flow by diffusion of Na ion in the neuronal cytoplasm. However, although highly successful in predicting and explaining many of the electric characteristics of the action potential, the HH model, nevertheless cannot accommodate the various non-electrical physical manifestations (mechanical, thermal and optical changes) that accompany action potential propagation, and for which there is ample experimental evidence. As such, the electrical conception of neuronal excitability appears to be incomplete and alternatives, aiming to improve, extend or even replace it, have been sought for. Commonly misunderstood as to their basic premises and the physical principles they are built on, and mistakenly perceived as a threat to the generally acknowledged explanatory power of the "classical" HH framework, these attempts to present a more complete picture of neuronal physiology, have met with fierce opposition from mainstream neuroscience and, as a consequence, currently remain underdeveloped and insufficiently tested. Here we present our perspective that this may be an unfortunate state of affairs as these different biophysics-informed approaches to incorporate also non-electrical signs of the action potential into the modeling and explanation of the nerve signal, in our view, are well suited to foster a new, more complete and better integrated understanding of the (multi)physical nature of neuronal excitability and signal transport and, hence, of neuronal function. In doing so, we will emphasize attempts to derive the different physical manifestations of the action potential from one common, macroscopic thermodynamics-based, framework treating the multiphysics of the nerve signal as the inevitable result of the collective material, i.e., physico-chemical, properties of the lipid bilayer neuronal membrane (in particular, the axolemma) and/or the so-called ectoplasm or membrane skeleton consisting of cytoskeletal protein polymers, in particular, actin fibrils. Potential consequences for our view of action potential physiology and role in neuronal function are identified and discussed.
PubMed: 37701723
DOI: 10.3389/fncel.2023.1232020 -
The Journal of Physiology Oct 2021In myelinated nerve fibres, action potentials are generated at nodes of Ranvier. These structures are located at interruptions of the myelin sheath, forming narrow gaps...
In myelinated nerve fibres, action potentials are generated at nodes of Ranvier. These structures are located at interruptions of the myelin sheath, forming narrow gaps with small rings of axolemma freely exposed to the extracellular space. The mammalian node contains a high density of Na channels and K -selective leakage channels. Voltage-dependent Kv1 channels are only present in the juxta-paranode. Recently, the leakage channels have been identified as K2P channels (TRAAK, TREK-1). K2P channels are K -selective 'background' channels, characterized by outward rectification and their ability to be activated, e.g. by temperature, mechanical stretch or arachidonic acid. We are only beginning to elucidate the peculiar functions of nodal K2P channels. I will discuss two functions of the nodal K2P-mediated conductance. First, at body temperature K2P channels have a high open probability, thereby inducing a resting potential of about -85 mV. This negative resting potential reduces steady-state Na channel inactivation and ensures a large Na inward current upon a depolarizing stimulus. Second, the K2P conductance is involved in nodal action potential repolarization. The identification of nodal K2P channels is exciting since it shows that the nodal K conductance is not a fixed value but can be changed: it can be increased or decreased by a broad range of K2P modulators, thereby modulating, for example, the resting potential. The functional importance of nodal K2P channels will be exemplified by describing in more detail the function of the K2P conductance increase by raising the temperature from room temperature to 37°C.
Topics: Action Potentials; Animals; Axons; Membrane Potentials; Myelin Sheath; Nerve Fibers, Myelinated
PubMed: 34425634
DOI: 10.1113/JP281723 -
Journal of Clinical Neurology (Seoul,... Mar 2023Peripheral neuropathies (PNs) are a common but poorly understood complication of chronic obstructive pulmonary disease (COPD). To clarify the initial trigger of a PN in...
BACKGROUND AND PURPOSE
Peripheral neuropathies (PNs) are a common but poorly understood complication of chronic obstructive pulmonary disease (COPD). To clarify the initial trigger of a PN in COPD, we investigated the excitability of peripheral nerves in patients with COPD.
METHODS
The automated nerve excitability test (NET) using the threshold-tracking paradigm was applied to 20 COPD patients. The recording protocol calculated the strength-duration time constant, threshold electrotonus (TE), current-threshold relationship, and recovery cycle (RC). Each NET parameter was compared with two control groups: normal controls group (NC group) and smokers without COPD group (smoker group).
RESULTS
In the motor NETs, the change in the threshold in the mid-depolarizing phase of TE (40-60 ms) was smaller in the COPD group (50.7%±1.2%, mean±SEM; =20) than in the NC group (54.5%±0.7%, =25; <0.01), as was the prominence of superexcitability in the RC (-22.6%±1.5% and -26.4%±1.1%, respectively; =0.04). There were no significant differences in the sensory NETs. Comparisons between the COPD and smoker groups (=25) also showed no differences in either the motor or sensory NETs.
CONCLUSIONS
The pattern of excitability in COPD revealed a membrane depolarization attributable to Na-K-ATPase failure in the axolemma of distal motor nerves. This finding suggests that chronic hypoxemia and adaptative process can alter axonal excitability and trigger a resultant neuropathic process that is antecedent to PN in COPD.
PubMed: 36854335
DOI: 10.3988/jcn.2022.0249 -
Frontiers in Molecular Biosciences 2021Around half of the traumatic brain injuries are thought to be axonal damage. Disruption of the cellular membranes, or alternatively cytoskeletal damage has been...
Around half of the traumatic brain injuries are thought to be axonal damage. Disruption of the cellular membranes, or alternatively cytoskeletal damage has been suggested as possible injury trigger. Here, we have used molecular models to have a better insight on the structural and mechanical properties of axon sub-cellular components. We modelled myelin sheath and node of Ranvier as lipid bilayers at a coarse grained level. We built ex-novo a model for the myelin. Lipid composition and lipid saturation were based on the available experimental data. The model contains 17 different types of lipids, distributed asymmetrically between two leaflets. Molecular dynamics simulations were performed to characterize the myelin and node-of-Ranvier bilayers at equilibrium and under deformation and compared to previous axolemma simulations. We found that the myelin bilayer has a slightly higher area compressibility modulus and higher rupture strain than node of Ranvier. Compared to the axolemma in unmyelinated axon, mechanoporation occurs at 50% higher strain in the myelin and at 23% lower strain in the node of Ranvier in myelinated axon. Combining the results with finite element simulations of the axon, we hypothesizes that myelin does not rupture at the thresholds proposed in the literature for axonal injury while rupture may occur at the node of Ranvier. The findings contribute to increases our knowledge of axonal sub-cellular components and help to understand better the mechanism behind axonal brain injury.
PubMed: 34250015
DOI: 10.3389/fmolb.2021.669897 -
Frontiers in Cellular Neuroscience 2021In the central nervous system, myelin is attached to the axon in the paranodal region by a trimolecular complex of Neurofascin155 (NF155) in the myelin membrane,...
In the central nervous system, myelin is attached to the axon in the paranodal region by a trimolecular complex of Neurofascin155 (NF155) in the myelin membrane, interacting with Caspr1 and Contactin1 on the axolemma. Alternative splicing of a single Neurofascin transcript generates several different Neurofascins expressed by several cell types, but NF155, which is expressed by oligodendrocytes, contains a domain in the third fibronectinIII-like region of the molecule that is unique. The immunoglobulin 5-6 domain of NF155 is essential for binding to Contactin1, but less is known about the functions of the NF155-unique third fibronectinIII-like domain. Mutations and autoantibodies to this region are associated with several neurodevelopmental and demyelinating nervous system disorders. Here we used Crispr-Cas9 gene editing to delete a 9 bp sequence of NF155 in this unique domain, which has recently been identified as a thrombin binding site and implicated in plasticity of the myelin sheath. This small deletion results in dysmyelination, eversion of paranodal loops of myelin, substantial enlargement of the nodal gap, a complete loss of paranodal septate junctions, and mislocalization of Caspr1 and nodal sodium channels. The animals exhibit tremor and ataxia, and biochemical and mass spectrometric analysis indicates that while NF155 is transcribed and spliced normally, the NF155 protein is subsequently degraded, resulting in loss of the full length 155 kDa native protein. These findings reveal that this 9 bp region of NF155 in its unique third fibronectinIII-like domain is essential for stability of the protein.
PubMed: 33815060
DOI: 10.3389/fncel.2021.576609 -
Neural Regeneration Research May 2022The formation of nerve bundles, which is partially regulated by neural cell adhesion molecule 1 (NCAM1), is important for neural network organization during peripheral...
The formation of nerve bundles, which is partially regulated by neural cell adhesion molecule 1 (NCAM1), is important for neural network organization during peripheral nerve regeneration. However, little is known about how the extracellular matrix (ECM) microenvironment affects this process. Here, we seeded dorsal root ganglion tissue blocks on different ECM substrates of peripheral nerve ECM-derived matrix-gel, Matrigel, laminin 521, collagen I, and collagen IV, and observed well-aligned axon bundles growing in the peripheral nerve ECM-derived environment. We confirmed that NCAM1 is necessary but not sufficient to trigger this phenomenon. A protein interaction assay identified collagen VI as an extracellular partner of NCAM1 in the regulation of axonal fasciculation. Collagen VI interacted with NCAM1 by directly binding to the FNIII domain, thereby increasing the stability of NCAM1 at the axolemma. Our in vivo experiments on a rat sciatic nerve defect model also demonstrated orderly nerve bundle regeneration with improved projection accuracy and functional recovery after treatment with 10 mg/mL Matrigel and 20 μg/mL collagen VI. These findings suggest that the collagen VI-NCAM1 pathway plays a regulatory role in nerve bundle formation. This study was approved by the Animal Ethics Committee of Guangzhou Medical University (approval No. GY2019048) on April 30, 2019.
PubMed: 34558529
DOI: 10.4103/1673-5374.324861 -
European Journal of Translational... Jul 2023Chronic Ataxic Neuropathy with anti-Disialosyl IgM Antibodies (CANDA) is a rare form of immune-mediated sensory ataxic neuropathy. We describe the case of a 45-year-old...
Chronic Ataxic Neuropathy with anti-Disialosyl IgM Antibodies (CANDA) is a rare form of immune-mediated sensory ataxic neuropathy. We describe the case of a 45-year-old man, who was diagnosed with CANDA in October 2018. Since then, he has been treated with monthly courses of intravenous immunoglobulin administration (IV Ig) and, in October 2022, he underwent plasmapheresis, reporting a sudden worsening of clinical and motor picture. After a new IV Ig cycle admission, the patient was hospitalized to perform intensive rehabilitation, involving two individual sessions per day (90 minutes each) for 5 days a week. During hospitalization it was registered a relevant improvement in the muscle strength of the lower limbs (LLs). Furthermore, progressive improvements were recorded both in patient's motor performance and in his level of autonomy in activities of daily living. These results had a positive impact on his quality of life and made it possible to reduce the frequency of IV Ig treatments. This is the first case in literature reporting the combined effect of rehabilitation treatment and medical therapy in CANDA neuropathy.
PubMed: 37522810
DOI: 10.4081/ejtm.2023.11557