Increase In Axon Diameter Research Articles

How do neurons age? A focused review on the aging of the microtubular cytoskeleton.

Aging is the leading risk factor for Alzheimer's disease and other neurodegenerative diseases. We now understand that a breakdown in the neuronal cytoskeleton, mainly underpinned by protein modifications leading to the destabilization of microtubules, is central to the pathogenesis of Alzheimer's disease. This is accompanied by morphological defects across the somatodendritic compartment, axon, and synapse. However, knowledge of what occurs to the microtubule cytoskeleton and morphology of the neuron during physiological aging is comparatively poor. Several recent studies have suggested that there is an age-related increase in the phosphorylation of the key microtubule stabilizing protein tau, a modification, which is known to destabilize the cytoskeleton in Alzheimer's disease. This indicates that the cytoskeleton and potentially other neuronal structures reliant on the cytoskeleton become functionally compromised during normal physiological aging. The current literature shows age-related reductions in synaptic spine density and shifts in synaptic spine conformation which might explain age-related synaptic functional deficits. However, knowledge of what occurs to the microtubular and actin cytoskeleton, with increasing age is extremely limited. When considering the somatodendritic compartment, a regression in dendrites and loss of dendritic length and volume is reported whilst a reduction in soma volume/size is often seen. However, research into cytoskeletal change is limited to a handful of studies demonstrating reductions in and mislocalizations of microtubule-associated proteins with just one study directly exploring the integrity of the microtubules. In the axon, an increase in axonal diameter and age-related appearance of swellings is reported but like the dendrites, just one study investigates the microtubules directly with others reporting loss or mislocalization of microtubule-associated proteins. Though these are the general trends reported, there are clear disparities between model organisms and brain regions that are worthy of further investigation. Additionally, longitudinal studies of neuronal/cytoskeletal aging should also investigate whether these age-related changes contribute not just to vulnerability to disease but also to the decline in nervous system function and behavioral output that all organisms experience. This will highlight the utility, if any, of cytoskeletal fortification for the promotion of healthy neuronal aging and potential protection against age-related neurodegenerative disease. This review seeks to summarize what is currently known about the physiological aging of the neuron and microtubular cytoskeleton in the hope of uncovering mechanisms underpinning age-related risk to disease.

Novel insights into axon diameter and myelin content in late childhood and adolescence.

White matter microstructural development in late childhood and adolescence is driven predominantly by increasing axon density and myelin thickness. Ex vivo studies suggest that the increase in axon diameter drives developmental increases in axon density observed with pubertal onset. In this cross-sectional study, 50 typically developing participants aged 8-18years were scanned using an ultra-strong gradient magnetic resonance imaging scanner. Microstructural properties, including apparent axon diameter $({d}_a)$, myelin content, and g-ratio, were estimated in regions of the corpus callosum. We observed age-related differences in ${d}_a$, myelin content, and g-ratio. In early puberty, males had larger ${d}_a$ in the splenium and lower myelin content in the genu and body of the corpus callosum, compared with females. Overall, this work provides novel insights into developmental, pubertal, and cognitive correlates of individual differences in apparent axon diameter and myelin content in the developing human brain.

Studying the Effect of Maternal Anemia and Neonatal Hematological Indices on Auditory Brainstem Responses of Newborn Babies

Purpose: Animal studies have shown the effect of maternal anemia (MA) and neonatal iron deficiency (ID) on the auditory system of young ones. However, the evidence supporting the same in human infants is inconclusive. Hence, the present study aims to investigate the effect of MA and neonatal iron status on the auditory brainstem responses (ABRs) of newborn babies. Materials and Methods: A total of 100 babies (gestational age ≥34 weeks) were divided into “Normal” group-57 babies without MA, “Mild” group-22 mild MA babies, and “Moderate” group-21 moderate MA babies. The ABR was recorded using 80 dBnHL click stimuli at 10 and 90 Hz repetition rates. Results: The results based on MA showed a significantly better presence of ABR peaks for the normal group than mild and moderate groups at a higher rate and no significant difference for latency and amplitude measures across the groups. The results based on neonatal hematological indices showed that the ABR measures were better in babies with probable ID which could be attributed to neural hyperactivity and an increase in axonal diameter leading to faster nerve conduction velocity. Conclusion: The auditory system maturation in newborn babies is influenced by maternal as well as neonatal iron status.

Demonstration of the protective effect of propofol in rat model of cisplatin-induced neuropathy.

Cisplatin is commonly used in the treatment of lung, genitourinary, and gastrointestinal cancers. Peripheral neuropathy is the most important side effect, leading to a decrease in the dose of cisplatin or its complete cessation in the early period. 16 rats were given cisplatin at a dose of 2.5 mg/ kg/day twice a week for 4 weeks to induce neuropathy model. The rats taking Cisplatin were divided into 2 groups. Group 1 rats (n = 8) were given 1 ml/kg/day 0.9 % NaCl intraperitoneally, and Group 2 rats were given 10 mg/kg/day Propofol intraperitoneally daily for 4 weeks. The remaining 8 rats served as the control group. At the end of the study, all animals were tested for motor functions. Blood samples were collected for the measurement of plasma lipid peroxidation (malondialdehyde; MDA), tumor necrosis factor (TNF-α), glutathione (GSH), IL-6 and HSP-70 levels. Electromyography findings revealed that compound muscle action potential (CMAP) amplitude was significantly higher in the cisplatin-Propofol group than in the cisplatin-saline group. Also, cisplatin-Propofol treated group showed significantly lower TNF-α, MDA and IL-6 levels and higher GSH and HSP-70 levels than cispalatin-Saline group (p < 0.01, p < 0.001). In addition, while the CMAP latency was decreased in the propofol group, the CMAP amplitude was increased, and a significant improvement was observed in the Inclined test scores. Besides, histological examinations showed an increase in axon diameter and NGF expression with Propofol treatment. This study demonstrated that Propofol exerts protective activity against cisplatin-induced neurotoxicity by increasing endogenous antioxidants and reducing lipid peroxidation and inflammation (Tab. 3, Fig. 4, Ref. 30). Text in PDF www.elis.sk Keywords: cisplatin, neuropathy, propofol, oxidative damage, ınflammation.

Postnatal Increases in Axonal Conduction Velocity of an Identified Drosophila Interneuron Require Fast Sodium, L-Type Calcium and Shaker Potassium Channels.

During early postnatal life, speed up of signal propagation through many central and peripheral neurons has been associated with an increase in axon diameter or/and myelination. Especially in unmyelinated axons postnatal adjustments of axonal membrane conductances is potentially a third mechanism but solid evidence is lacking. Here, we show that axonal action potential (AP) conduction velocity in the Drosophila giant fiber (GF) interneuron, which is required for fast long-distance signal conduction through the escape circuit, is increased by 80% during the first day of adult life. Genetic manipulations indicate that this postnatal increase in AP conduction velocity in the unmyelinated GF axon is likely owed to adjustments of ion channel expression or properties rather than axon diameter increases. Specifically, targeted RNAi knock-down of either Para fast voltage-gated sodium, Shaker potassium (Kv1 homologue), or surprisingly, L-type like calcium channels counteracts postnatal increases in GF axonal conduction velocity. By contrast, the calcium-dependent potassium channel Slowpoke (BK) is not essential for postnatal speeding, although it also significantly increases conduction velocity. Therefore, we identified multiple ion channels that function to support fast axonal AP conduction velocity, but only a subset of these are regulated during early postnatal life to maximize conduction velocity. Despite its large diameter (∼7 µm) and postnatal regulation of multiple ionic conductances, mature GF axonal conduction velocity is still 20–60 times slower than that of vertebrate Aβ sensory axons and α motoneurons, thus unraveling the limits of long-range information transfer speed through invertebrate circuits.

Oligodendrogenesis and myelinogenesis during postnatal development effect of glatiramer acetate.

Myelinogenesis in the mammal nervous system occurs predominantly postnatally. Glatiramer acetate (GA), a drug for the treatment for multiple sclerosis (MS), has been shown to induce immunomodulation and neuroprotection in the inflamed CNS in MS and in experimental autoimmune encephalomyelitis (EAE). Here we investigated whether GA can affect myelinogenesis and oligodendrogenesis in the developing nervous system under nonpathological conditions. Towards this end we studied myelination in mice injected daily by GA, at postnatal Days 7-21. Immunohistological and ultrastructural analyses revealed significant elevation in the number of myelinated axons as well as in the thickness of the myelin encircling them and their resulting g-ratios, in spinal cords of GA-injected mice compared with their PBS-injected littermates, at postnatal Day 14. Elevation in myelinated axons was detected also in the peripheral ventral roots of the motor nerves. GA induced also an increase in axonal diameter, implying an effect on the overall development of the nervous system. A prominent elevation in the amount of progenitor oligodendrocytes and their BrdU incorporation, as well as in mature oligodendrocytes indicated that the effect of GA is linked to increased proliferation and differentiation along the oligodendroglial maturation cascade. In addition, elevation in insulin-like growth factor (IGF-1) and brain-derived neurotrophic factor (BDNF) was found in the white matter of the GA-injected mice. Furthermore, a functional advantage in rotating rod test was exhibited by GA-injected mice over their littermates at postnatal Day 21. These cumulative findings corroborate the beneficial effect of GA on oligodendrogenesis and myelination.

Correlation between electrophysiological properties, morphological maturation, and olig gene changes during postnatal motor tract development

This study investigated electrophysiological and histological changes as well as alterations of myelin relevant proteins of descending motor tracts in rat pups. Motor-evoked potentials (MEPs) represent descending conducting responses following stimulation of the motor cortex to responses being elicited from the lower extremities. MEP responses were recorded biweekly from postnatal (PN) week 1 to week 9 (adult). MEP latencies in PN week 1 rats averaged 23.7 ms and became shorter during early maturation, stabilizing at 6.6 ms at PN week 4. During maturation, the conduction velocity (CV) increased from 2.8 ± 0.2 at PN week 1 to 35.2 ± 3.1 mm/ms at PN week 8. Histology of the spinal cord and sciatic nerves revealed progressive axonal myelination. Expression of the oligodendrocyte precursor markers PDGFRα and NG2 were downregulated in spinal cords, and myelin-relevant proteins such as GalC, CNP, and MBP increased during maturation. Oligodendrocyte-lineage markers Olig2 and MOG, expressed in myelinated oligodendrocytes, peaked at PN week 3 and were downregulated thereafter. A similar expression pattern was observed in neurofilament M/H subunits that were extensively phosphorylated in adult spinal cords but not in neonatal spinal cords, suggesting an increase in axon diameter and myelin formation. Ultrastructural morphology in the ventrolateral funiculus (VLF) showed axon myelination of the VLF axons (99.3%) at PN week 2, while 44.6% were sheathed at PN week 1. Increased axon diameter and myelin thickness in the VLF and sciatic nerves were highly correlated to the CV (rs > 0.95). This suggests that MEPs could be a predicator of morphological maturity of myelinated axons in descending motor tracts.

Effects of Cellular Adaptations to Partial Demyelination on Spike Patterns in a Model Axon

In a computational model, axons undergoing demyelination can produce a wide variety of spike patterns ranging from conduction failure to high-frequency bursting. We have simulated cellular adaptations to partial demyelination to understand what an axon might gain from adaptations to changes in excitability. Observed clinical phenomena in multiple sclerosis include an increase in axon diameter and the aggregation of mitochondria during demyelination. We, therefore, examined the effect of axon diameter swelling and increased activity of Na-K pumps on axonal excitability.

Variation of the neurofilament medium KSP repeat sub-domain across mammalian species: implications for altering axonal structure

The evolution of larger mammals resulted in a corresponding increase in peripheral nerve length. To ensure optimal nervous system functionality and survival, nerve conduction velocities were likely to have increased to maintain the rate of signal propagation. Increases of conduction velocities may have required alterations in one of the two predominant properties that affect the speed of neuronal transmission: myelination or axonal diameter. A plausible mechanism to explain faster conduction velocities was a concomitant increase in axonal diameter with evolving axonal length. The carboxy terminal tail domain of the neurofilament medium subunit is a determinant of axonal diameter in large caliber myelinated axons. Sequence analysis of mammalian orthologs indicates that the neurofilament medium carboxy terminal tail contains a variable lysine-serine-proline (KSP) repeat sub-domain flanked by two highly conserved sub-domains. The number of KSP repeats within this region of neurofilament medium varies among species. Interestingly, the number of repeats does not change within a species, suggesting that selective pressure conserved the number of repeats within a species. Mapping KSP repeat numbers onto consensus phylogenetic trees reveals independent KSP expansion events across several mammalian clades. Linear regression analyses identified three subsets of mammals, one of which shows a positive correlation in the number of repeats with head-body length. For this subset of mammals, we hypothesize that variations in the number of KSP repeats within neurofilament medium carboxy terminal tail may have contributed to an increase in axonal caliber, increasing nerve conduction velocity as larger mammals evolved.

Node of Ranvier formation on motoneurons in vitro

One of the most significant interactions between Schwann cells and neurons is myelin sheath formation. Myelination is a vertebrate adaptation that enables rapid conduction of action potentials without a commensurate increase in axon diameter. In vitro neuronal systems provide a unique modality to study both factors influencing myelination and diseases associated with myelination. Currently, no in vitro system for motoneuron myelination by Schwann cells has been demonstrated. This work details the myelination of motoneuron axons by Schwann cells, with complete Node of Ranvier formation, in a defined in vitro culture system. This defined system utilizes a novel serum-free medium in combination with the non-biological substrate, N-1[3 (trimethoxysilyl) propyl] diethylenetriamine (DETA). The myelinated segments and nodal proteins were visualized and quantified using confocal microscopy. This defined system provides a highly controlled, reproducible model for studying Schwann cell interactions with motoneurons as well as the myelination process and its effect on neuronal plasticity. Furthermore, an in vitro system that would allow studies of motoneuron myelination would be beneficial for understanding peripheral demyelinating neuropathies such as diabetes induced peripheral neuropathy and could lead to a better understanding of CNS demyelinating diseases like multiple sclerosis, as well as neuromuscular junction maturation and maintenance.

Axones et cellules de Schwann… si loin, si proches

Myelination was a major step in the evolution of the nervous system. Appearing first in jaw fish, myelination allows the fast and secure propagation of action potentials at a low energetic cost, and without exaggerated increase in axonal diameter. In the peripheral nervous system of mammals, myelination results from the tight interactions between Schwann cells and axons, leading to the formation of highly differentiated domains along the axon. The molecular determinants of these interactions are starting to be well identified. Their understanding provides a precise framework to interpret the defects, which occur in pathological circumstances. This review summarizes the present state of knowledge concerning axoglial interactions in peripheral nerves.

Postnatal changes in enteric plexus axonal thickness

Chronological age has not always been an accurate predictor of gut motility in newborns. We hypothesized that the enteric plexus is immature at birth. We studied whole-mount preparations of the myenteric plexus in pigs from mid-point of gestation to adulthood. Distal large bowel whole-mount preparations of the myenteric plexus were stained using ACHE histochemistry in five pigs from six different age groups (60 and 90 days gestation, newborn, 4 and 12 weeks old, and adult pigs). With the aid of light micrographs and Image J program the axonal diameter, distance between ganglia, neuronal size and neuronal nucleus size were measured. Statistical significance was measured using one-way ANOVA test. There was significant increase in axonal diameter and interganglionic distance, with increasing age in the myenteric plexus of rectum in pigs (P < 0.05). Neuronal cell size and nucleus size of the enteric neurons also increased with age, but was not statistically significant. This study shows for the first time that the axonal thickness in the enteric myenteric plexus undergoes striking changes during the first 12 weeks of life in piglets. Assessment of axonal thickness in rectal biopsies may be a valuable morphological feature in diagnosing functional intestinal obstruction in infants.

Collagen—Chitosan Nerve Guides for Peripheral Nerve Repair: A Histomorphometric Study

Currently a wide variety of polymer materials are being applied to fabricate nerve guide tubes to repair injured peripheral nerves. In this study we have examined whether collagen-chitosan nerve guides promotes nerve repair compared to chitosan nerve guides using histological analysis. Results indicates that the enclosed structure of the nerve guide both promotes and supports axonal sprouting. Collagen-chitosan guides improved axonal maturation measured by a significant increase in axon diameter and axon area. These findings indicate that the collagen-chitosan nerve guides can be applied to repair severed peripheral nerve ends.

Cytoskeletal organization of the developing mouse olfactory nerve layer

Olfactory sensory neuron (OSN) axonal extension and targeting occur within the olfactory nerve layer (ONL) of the olfactory bulb (OB). The ONL can be differentiated into sublaminae: the outer (ONLo), where axons broadly target regions of the OB in tight fascicles, and inner (ONLi), where axons perform final targeting in loosely organized fascicles. During perinatal development, cadherin-2 and its binding partner, gamma-catenin, are preferentially expressed by OSN axons in the ONLo vs. the ONLi. Given the expression of these cytoskeleton-associated molecules, we hypothesized that cytoskeletal elements of OSN axons may be differentially expressed across the ONL. We therefore examined cytoskeletal organization of OSN axons in the ONL, focusing on the day of birth (P0). We show that microfilaments, microtubules, and the intermediate filament (IF) vimentin are homogeneously expressed across the ONL at P0. In contrast, the IFs peripherin and alpha-internexin are preferentially localized to the ONLo at P0, with alpha-internexin expressed by a restricted subset of OSNs. We also show that OSN axons in the ONLo are significantly smaller than those in the ONLi. The data demonstrate that, as OSN axons begin to exit the ONLo and target a specific region of the OB, there is a down-regulation of cytoskeletal elements and bound extracellular adhesion molecules. The increase in axon diameter may reflect additional mechanisms involved in glomerular targeting or the formation of the large terminal boutons of OSN axons within glomeruli.

Nerve pathology in the type 1 diabetic dog: effects of treatment with sulindac.

The purpose of this study was to define pathological abnormalities in the peripheral nerve of a large animal model of long-duration type 1 diabetes and also to determine the effects of treatment with sulindac. Detailed morphometric studies were performed to define nerve fiber and endoneurial capillary pathology in 6 control dogs, 6 type 1 diabetic dogs treated with insulin, and 6 type 1 diabetic dogs treated with insulin and sulindac for 4 years. Myelinated fiber and regenerative cluster density showed a non-significant trend toward a reduction in diabetic compared to control animals, which was prevented by treatment with sulindac. Unmyelinated fiber density did not differ among groups. However, diabetic animals showed a non-significant trend toward an increase in axon diameter (p < 0.07), with a shift of the size frequency distribution towards larger axons, which was not prevented by treatment with sulindac. Endoneurial capillary density and luminal area showed a non-significant trend toward an increase in diabetic animals, which was prevented with sulindac treatment. Endoneurial capillary basement membrane area was significantly increased (p < 0.05) in diabetic animals, but was not prevented with sulindac treatment. We conclude that the type 1 diabetic dog demonstrates minor structural abnormalities in the nerve fibers and endoneurial capillaries of the sciatic nerve, and treatment with sulindac ameliorates some but not all of these abnormalities.

Morphometric analysis of the myelin-associated oligodendrocytic basic protein-deficient mouse reveals a possible role for myelin-associated oligodendrocytic basic protein in regulating axonal diameter

Myelin-associated oligodendrocytic basic protein is a member of the proteins constituting the central nervous system myelin. By morphometric analysis, we demonstrated that axons of myelin-associated oligodendrocytic basic protein-deficient mice had larger diameters and more myelin lamellae as compared to those of wild-type mice at the same age. It is known that the number of myelin lamellae increases linearly with axonal diameter, and that the rate of radial axonal growth is the factor controlling the rate of myelin formation. In line with these observations, we found that the regression line for axonal diameter and the number of myelin lamellae in myelin-associated oligodendrocytic basic protein-deficient mice appeared to be identical to that in wild-type mice, indicating that the increase in the number of myelin lamellae was the result of the increase in axonal diameter. Furthermore, we generated myelin basic protein/myelin-associated oligodendrocytic basic protein-double-deficient mice through mating myelin-associated oligodendrocytic basic protein-deficient mice with shiverer mice, an autosomal recessive mutant characterized by a lack of all isoforms of myelin basic protein. With these knock-out mice, we showed that axons of the double-deficient mice had larger diameters and smaller form factor, an index of the deformation of the fiber contour, in ensheathed fibers than those of shiverer mice, although there was no difference in axonal diameter of unmyelinated fibers between them. Taken together, myelin-associated oligodendrocytic basic protein seemed to play a role in controlling axonal diameter and in keeping axons round.

The single neurofilament subunit of the lamprey forms filaments and regulates axonal caliber and neuronal size in vivo.

Neurofilaments (NFs) are composed of a heteropolymer of three related subunits in mammalian neurons, where they are a major component of the cytoskeleton in large neurons and are thought to regulate axonal diameter. NFs in the lamprey, while ultrastructurally and functionally indistinguishable from mammalian NFs, are polymers of a single subunit protein, NF180. In this study, we use the simplicity of lamprey NFs and the accessibility of the lamprey central nervous system (CNS) to examine the effects of overproducing NFs in an identified giant neuron in vivo, and thus to elucidate the role of NFs in regulating neuronal size and axonal caliber in the vertebrate CNS. We show that overexpression of NF180 tagged with a variant of Green Fluorescent Protein (EYFP) in identified lamprey neurons (ABCs) and in human neuroblastoma (NB2a) cells results in the assembly of exogenous NF180 into ultrastructurally normal NFs that are tightly packed and unphosphorylated. These accumulate in the somata of NB2a cells and produce somatic swelling by 3 days post-transfection. NF180 overexpression in lamprey ABCs in vivo causes exogenous NFs to accumulate in ABC axons, somata, and dendrites, and induces a significant increase in axonal diameter without increasing axonal NF packing density. Overexpression of EYFP alone has none of these effects. We conclude that NF180 normally plays a critical role in determining axonal caliber in ABCs and may influence neuronal size in situations where NFs accumulate in the soma, such as after axonal injury.

Fine structure and development of dorsal root ganglion neurons and Schwann cells in the newborn opossumMonodelphis domestica

The aim of these experiments was to determine the state of maturity of dorsal root ganglia and axons in opossums (Monodelphis domestica) at birth and to assess quantitatively changes that occur in early life. Counts made of dorsal root ganglion cells at cervical levels showed that the numbers were similar in newborn and adult animals, approximately 1,600 per ganglion. In cervical dorsal root ganglia of newborn animals, division of neuronal precursors cells had ceased. The number of axons in cervical dorsal roots was similar in newborn and adult animals (about 4,500). For each ganglion cell body, approximately three axons were counted in the dorsal root. At birth, dorsal roots contained several bundles about 30 microns in diameter consisting of small axons (0.05-2 microns in diameter). A few non-neural cells were identified as Schwann cell perikarya, each enclosing a number of neurites. Later, marked changes occurred in Schwann cells and in their relationship to axons in the roots. Thus, at 12 days, an increase occurred in the number of Schwann cells and fibroblasts, and the bundles had enlarged to about 80 microns with little increase in axon diameter (0.1-2 microns). By 18 days, the bundles were larger, and myelination had already started. At 23 days, the dorsal root contained more than 500 myelinated axons that could reach 5 microns in diameter. The adult dorsal root enclosed about 900 myelinated axons. Throughout this time, the relationship between the Schwann cells and axons changed. Together, these results indicate that the number of axons and cell bodies of sensory dorsal root ganglia in opossum do not show major changes after birth. In addition, these results set the stage for quantitative studies of regeneration of dorsal column fibers in injured neonatal opossum nervous system.

Developmental and pathological changes at the node and paranode in human sural nerves.

The nodes and paranodes of peripheral nerve fibers are complex structures that are especially prone to artificial and pathological changes which have to be distinguished from normal developmental changes. Alterations during normal development are mainly caused by an increase in axonal diameter and myelin sheath thickness. The nodal, and paranodal axon diameters in human sural nerves reach their adult values at 3-5 years of age, simultaneously to the internodal diameter. The ratio between internodal and paranodal axon diameters remain relatively constant, with an average value of 1.8 to 2.0 (range: 1.6 to 2.5). Despite a considerable increase of the number of myelin lamellae, the length of the paranodal myelin sheath attachment zone at the axon does not increase correspondingly, because of (1) attenuation of the terminal myelin loops, (2) separation of some of these from the axolemma, and their piling up in the paranode. Separation of variable numbers of terminal myelin loops from the underlying axolemma results in the formation of the spines on the "double bracelet épineux" of Nageotte, while the transverse bands of these loops disappear. The adaptation of the paranodal myelin sheath to axonal expansion during development probably occurs by uneven gliding of the paranodal myelin loops simultaneously with internodal slippage of myelin lamellae. Artificial changes are caused by insufficient fixation or mechanical stress during excision and further handling (cutting, dedydrating, embedding) of nerves whereas pathological changes may be induced by a multitude of causes. An attempt to classify these changes is presented in Table 2.

Developmental and pathological changes at the node and paranode in human sural nerves

The nodes and paranodes of peripheral nerve fibers are complex structures that are especially prone to artificial and pathological changes which have to be distinguished from normal developmental changes. Alterations during normal development are mainly caused by an increase in axonal diameter and myelin sheath thickness. The nodal, and paranodal axon diameters in human sural nerves reach their adult values at 3–5 years of age, simultaneously to the internodal diameter. The ratio between internodal and paranodal axon diameters remain relatively constant, with an average value of 1.8 to 2.0 (range: 1.6 to 2.5). Despite a considerable increase of the number of myelin lamellae, the length of the paranodal myelin sheath attachment zone at the axon does not increase correspondingly, because of (1) attenuation of the terminal myelin loops, (2) separation of some of these from the axolemma, and their piling up in the paranode. Separation of variable numbers of terminal myelin loops from the underlying axolemma results in the formation of the spines on the “double bracelet épineux” of Nageotte, while the transverse bands of these loops disappear. The adaptation of the paranodal myelin sheath to axonal expansion during development probably occurs by uneven gliding of the paranodal myelin loops simultaneously with internodal slippage of myelin lamellae. Artificial changes are caused by insufficient fixation or mechanical stress during excision and further handling (cutting, dedydrating, embedding) of nerves whereas pathological changes may be induced by a multitude of causes. An attempt to classify these changes is presented in Table 2. © 1996 Wiley-Liss, Inc.