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Pituitary adenylyl cyclase-activating polypeptide (PACAP) is a bioactive peptide with diverse effects in the nervous system. The present study investigated whether stimulation of PACAP receptors (PACAPRs) induces responses in neurons and satellite cells of the superior cervical ganglia (SCG), with special reference to intracellular Ca 2+ ([Ca 2+ ] i ) changes. The expression of PACAPRs in SCG was detected by reverse transcription-PCR. PACAP type 1 receptor (PAC1R), vasoactive intestinal peptide receptor type (VPAC)1R, and VPAC2R transcripts were expressed in SCG, with PAC1R showing the highest levels. Confocal microscopy analysis revealed that PACAP38 and PACAP27 induced an increase in [Ca 2+ ] i in SCG, first in satellite cells and subsequently in neurons. Neither extracellular Ca 2+ removal nor Ca 2+ channel blockade affected the PACAP38-induced increase in [Ca 2+ ] i in satellite cells; however, this was partly inhibited in neurons. U73122 or xestospongin C treatment completely and partly abrogated [Ca 2+ ] i changes in satellite cells and in neurons, respectively, whereas VPAC1R and VPAC2R agonists increased [Ca 2+ ] i in satellite cells only. This is the first report demonstrating the expression of PACAPRs specifically, VPAC1 and VPAC2 in SCG and providing evidence for PACAP38-induced [Ca 2+ ] i changes in both satellite cells and neurons via Ca 2+ mobilization.

Myelinogenesis is a complex process that involves substantial and dynamic changes in plasma membrane architecture and myelin interaction with axons. Highly ramified processes of oligodendrocytes in the central nervous system (CNS) make axonal contact and then extrapolate to wrap around axons and form multilayer compact myelin sheathes. Currently, the mechanisms governing myelin sheath assembly and axon selection by myelinating cells are not fully understood. Here, we generated a transgenic mouse line expressing the membrane-anchored green fluorescent protein (mEGFP) in myelinating cells, which allow live imaging of details of myelinogenesis and cellular behaviors in the nervous systems. mEGFP expression is driven by the promoter of 2'-3'-cyclic nucleotide 3'-phosphodiesterase (CNP) that is expressed in the myelinating cell lineage. Robust mEGFP signals appear in the membrane processes of oligodendrocytes in the CNS and Schwann cells in the peripheral nervous system (PNS), wherein mEGFP expression defines the inner layers of myelin sheaths and Schmidt-Lanterman incisures in adult sciatic nerves. In addition, mEGFP expression can be used to track the extent of remyelination after demyelinating injury in a toxin-induced demyelination animal model. Taken together, the membrane-anchored mEGFP expression in the new transgenic line would facilitate direct visualization of dynamic myelin membrane formation and assembly during development and process remodeling during remyelination after various demyelinating injuries.

Inwardly rectifying potassium (Kir) channel Kir4.1 (also called Kcnj10) is expressed in various cells such as satellite glial cells. It is suggested that these cells would absorb excess accumulated K(+) from intercellular space which is surrounded by these cell membranes expressing Kir4.1. In the vestibular system, loss of Kir4.1 results in selective degeneration of type I hair cells despite normal development of type II hair cells. The mechanisms underlying this developmental disorder have been unclear, because it was thought that Kir4.1 is only expressed in glial cells throughout the entire nervous system. Here, we show that Kir4.1 is expressed not only in glial cells but also in neurons of the mouse vestibular system. In the vestibular ganglion, Kir4.1 mRNA is transcribed in both satellite cells and neuronal somata, whereas Kir4.1 protein is expressed only in satellite cells. On the other hand, in the vestibular sensory epithelia, Kir4.1 protein is localized at the calyx endings of vestibular afferents, which surround type I hair cells. Kir4.1 protein expression in the vestibular sensory epithelia is detected beginning after birth, and its localization gradually adopts a calyceal shape until type I hair cells are mature. Kir4.1 localized at the calyx endings may play a role in the K(+)-buffering action of vestibular afferents surrounding type I hair cells., (Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.)

In sensory ganglia each nerve cell body is usually enveloped by a satellite glial cell (SGC) sheath, sharply separated from sheaths encircling adjacent neurons by connective tissue. However, following axon injury SGCs may form bridges connecting previously separate perineuronal sheaths. Each sheath consists of one or several layers of cells that overlap in a more or less complex fashion; sometimes SGCs form a perineuronal myelin sheath. SGCs are flattened mononucleate cells containing the usual cell organelles. Several ion channels, receptors and adhesion molecules have been identified in these cells. SGCs of the same sheath are usually linked by adherent and gap junctions, and are functionally coupled. Following axon injury, both the number of gap junctions and the coupling of SGCs increase markedly. The apposed plasma membranes of adjacent cells are separated by 15-20 nm gaps, which form a potential pathway, usually long and tortuous, between connective tissue and neuronal surface. The boundary between neuron and SGC sheath is usually complicated, mainly by many projections arising from the neuron. The outer surface of the SGC sheath is covered by a basal lamina. The number of SGCs enveloping a nerve cell body is proportional to the cell body volume; the volume of the SGC sheath is proportional to the volume and surface area of the nerve cell body. In old animals, both the number of SGCs and the mean volume of the SGC sheaths are significantly lower than in young adults. Furthermore, extensive portions of the neuronal surface are not covered by SGCs, exposing neurons of aged animals to damage by harmful substances.

In order to explore neuroglial relationships in a simple nervous system, the ultrastructure of crayfish stretch receptor, which consists of only two sensory neurons enveloped by satellite glial cells, was studied. Neuronal Golgi complex was oriented such that its output trans-Golgi network usually faced the bundles of microtubules within the neuronal cytoplasm and very rarely to the outer membrane. Therefore, it participates mainly in the processing of proteins transported along microtubules to distal neuron parts rather than those transported to glial cells. Structural triads of submembrane cisterns-vesicles-mitochondria were involved in formation of glial protrusions into the neuronal cytoplasm. The double-wall vesicles within the neuron body were the captured parts of such glial protrusions. Glial protrusions and double-wall vesicles facilitated the neuroglial transport and large-scale delivery of the glial material into the neuron. The neuroglial transport could also be performed by diffusion across the intercellular space. These data indicate the significant neuroglial exchange with cellular components.

Several lines of evidence indicate that peripheral 5-HT2A receptors are involved in the development of inflammatory and neuropathic pain. However, their localization in sensory cell bodies is not accurately known. We therefore studied 5-HT2A receptor distribution in rat lumbar dorsal root ganglia using immunocytochemistry. Forty percent of L3 lumbar dorsal root ganglion cells were immunoreactive for 5-HT2A receptor. Most were small- to medium-sized cell bodies. Double-labeled experiments revealed that they expressed various chemical phenotypes. The smaller 5-HT2AR cell bodies often bind the isolectin B4 although some 5-HT2AR cell bodies also express substance P (SP). Many 5-HT2A-positive small dorsal root ganglion cells expressed the capsaicin receptor transient receptor potential vanilloid type 1 receptor (TRPV1), confirming their nociceptive nature. In addition, a few large cell bodies were labeled for 5-HT2A, and they also expressed NF200 suggesting that they were at the origin of Adelta or Abeta fibers. A total absence of double labeling with parvalbumin showed that they were not proprioceptors. 5-HT2A immunoreactivity in dorsal root ganglia cells was found in the cytoplasm and along the plasma membrane at the interface between sensory cell and the adjacent satellite cells; this distribution was confirmed under the electron microscope, and suggested a functional role for the 5-HT2A receptor at these sites. We therefore investigated the presence of 5-HT and 5-HIAA in lumbar dorsal root ganglia by high performance liquid chromatography. There were 5.75+/-0.80 ng 5-HT and 3.19+/-0.37 ng 5-hydroxyindoleacetic acid (5-HIAA) per mg of protein with a ratio 5-HIAA/5-HT of 0.67+/-0.10, similar to values typically observed in brain tissues. These findings suggest that 5-HT, via the 5-HT2AR, may be involved in the peripheral control of sensory afferents, mainly unmyelinated nociceptors and to a lesser extent neurons with Adelta or Abeta fibers, and in the control of cellular excitability of some dorsal root cell bodies through a paracrine mechanism of action.

The amygdala displays neuronal cell loss and gliosis in human temporal lobe epilepsy (TLE). Therefore, we investigated a certain type of gliosis, called satellitosis, in the lateral amygdala (LA) of TLE patients with Ammon's horn sclerosis (AHS, n = 15) and non-AHS (n = 12), and in autopsy controls. Satellite cells were quantified using light and electron microscopy at the somata of Nissl-stained and glutamic acid decarboxylase-negative projection neurons, and their functional properties were studied using electrophysiology. Non-AHS cases suffered from ganglioglioma, cortical dysplasia, Sturge-Weber syndrome, astrocytoma WHO III-IV, Rasmussen's encephalitis, cerebral infarction and perinatal brain damage. TLE cases with AHS had a more prominent satellitosis as compared to non-AHS and/or autopsy cases, which correlated with epilepsy duration but not age. At ultrastructural level, the predominant type of satellite cells occurring in both AHS and non-AHS cases displayed a dark cytoplasm and an irregularly shaped dark nucleus, whereas perineuronal glial cells with a light cytoplasm and light oval nucleus were much rarer. Satellite cells expressed time- and voltage-dependent transmembrane currents as revealed by patch-clamp recordings typical for 'complex' glia, although only 44% of satellite cells were immunostained for the chondroitin sulfate proteoglycan NG2. Together, the perineuronal cells described here were a heterogenous cell population regarding their NG2 expression, although they resembled NG2 cells rather than bona fide oligodendrocytes and astrocytes based on their ultrastructural and electrophysiological characteristics. Thus, perineuronal satellitosis as studied in the LA seems to be a hallmark of AHS-associated TLE pathology in patients suffering from intractable epilepsy.

The inward-rectifier K(+) channel Kir4.1 is responsible for maintaining cochlear homeostasis and restoring neural excitability. The large-conductance calcium-activated K(+) channel (BK(Ca)) plays a key role in phase locking signals in the mammalian inner ear. To evaluate the influence of mitochondrial dysfunction on the expression and subcellular localization of these channels, 3-nitropropionic acid (3-NP) was administered to rat round window membranes for 30 min. Auditory brainstem response was measured both before and 2 hr after 3-NP administration. Immunofluorescent confocal microscopy was used to measure the expression and subcellular localization of Kir4.1 and BK(Ca). Alexa Fluor 568-labeled bovine serum albumin (BSA) was applied to round window membranes as a tracer to explore the cochlear distribution of drug delivery and was detected in the lateral wall, spiral ganglion, cochlear nerve, and organ of Corti. Hearing loss of 23 (+/-4.4 SE) and 58 (+/-6.7 SE) dB developed in rats treated with 0.3 and 0.5 mol/liter of 3-NP, respectively. BK(Ca) was visualized in the cellular membrane and cytoplasm in the upper and middle region of inner hair cells, and it was not affected by 3-NP. Kir4.1 was detected in intermediate cells of the stria, Deiter's cells, and spiral ganglion satellite cells. Kir4.1 failed to reach the perineural cytoplasm of the satellite cells after 3-NP treatment. The results of this study suggest that mitochondrial dysfunction disrupts trafficking of Kir4.1 in spiral ganglion satellite cells., (2008 Wiley-Liss, Inc.)

Peripheral glial cells consist of satellite, enteric glial, and Schwann cells. In dorsal root ganglia, besides pseudo-unipolar neurons, myelinated and nonmyelinated fibers, macrophages, and fibroblasts, satellite cells also constitute the resident components. Information on satellite cells is not abundant; however, they appear to provide mechanical and metabolic support for neurons by forming an envelope surrounding their cell bodies. Although there is a heterogeneous population of neurons in the dorsal root ganglia, satellite cells have been described to be a homogeneous group of perineuronal cells. Our objective was to characterize the ultrastructure, immunohistochemistry, and histochemistry of the satellite cells of the dorsal root ganglia of 17 adult 3-4-month-old Wistar rats of both genders. Ultrastructurally, the nuclei of some satellite cells are heterochromatic, whereas others are euchromatic, which may result from different amounts of nuclear activity. We observed positive immunoreactivity for S-100 and vimentin in the cytoplasm of satellite cells. The intensity of S-100 protein varied according to the size of the enveloped neuron. We also noted that vimentin expression assumed a ring-like pattern and was preferentially located in the cytoplasm around the areas stained for S-100. In addition, we observed nitric oxide synthase-positive small-sized neurons and negative large-sized neurons equal to that described in the literature. Satellite cells were also positive for NADPH-diaphorase, particularly those associated with small-sized neurons. We conclude that all satellite cells are not identical as previously thought because they have different patterns of glial marker expression and these differences may be correlated with the size and function of the neuron they envelope.

Skeletal muscle satellite cells play an essential role in muscle regeneration and exercise adaptation. In recent years atypical myogenic progenitors (non-satellite-cell muscle stem cells) have been identified in skeletal muscle and have been hypothesized to play an important role in the process of muscle regeneration. It remains unknown, however, whether any populations other than satellite cells play a significant role in repair and adaptation following exercise-induced damage. We assessed the response of the satellite cell population and the CD45+:Sca-1+ cell population, previously shown to support muscle regeneration following cardiotoxin-induced injury, after acute eccentrically biased exercise in wild-type mice. We observed evidence of focal muscle damage and repair following the exercise protocol using electron microscopy, hematoxylin-eosin staining, and single-fiber analysis. In addition, we observed an approximately sixfold increase in the number of Myf5-expressing cells by 48 h, which remained elevated until at least 96 h following exercise. We did not, however, observe any significant expansion of the CD45+:Sca-1+ cell population or commitment of resident CD45+:Sca-1+ cells to the myogenic lineage. Furthermore, expression of Wnt gene family members, previously associated with myogenic specification of CD45+:Sca-1+ cells, did not differ following exercise. Therefore, we conclude that muscle satellite cells are the primary responders to exercise-induced stress and that the CD45+:Sca-1+ myogenic progenitors do not contribute to muscle repair/adaptation following exercise.

We studied quantitative changes in mitochondria of perineuronal satellite cell sheaths (SCSs) of rabbit spinal ganglia from young to extremely advanced age (1, 3.6, 6.7 and 8.8 years). The mitochondrial structure did not differ in the four age groups, while mitochondrial size increased progressively and significantly with age. The mean percentage of cytoplasmic volume occupied by mitochondria decreased progressively and significantly from young to old animals. This decrease was mainly due to a progressive and significant reduction in the total mitochondrial volume. Lipofuscin accumulation had a negligible influence on this reduction. These results suggest that the ability of SCSs to produce energy decreases with age and that the reduced ability of spinal ganglion neurons to respond to high energy demands in old age may be in part due to the diminished contribution of perineuronal satellite cells., (Copyright 2007 S. Karger AG, Basel.)

The volumes of the nerve cell bodies and those of the enveloping satellite cell sheaths from spinal ganglia were determined by morphometric methods applied to electron micrographs in young, adult, old and very old rabbits. The mean volume of the nerve cell bodies increased progressively with age; this is probably related to the increase with age of the body size of the rabbits studied. The mean volume of the satellite cell sheaths did not differ significantly in young, adult and old animals, but was significantly smaller in very old animals. It is extremely unlikely that this marked reduction in the volume of the satellite cell sheath is the result of a pathological process. The mean value of the volume ratio between the satellite cell sheaths and the related nerve cell bodies did not differ significantly in young and adult animals, but was significantly smaller in old and very old animals. This ratio was particularly low in very old animals. Our analysis showed that in each age group the volume of the satellite cell sheath is linearly related to the volume of the related nerve cell body. This result suggests that in rabbit spinal ganglia the quantitative relations between glial and nervous tissue are tightly controlled throughout life. It is suggested that ganglionic neurons release signals to influence and control the volume of their associated glial tissue. Since satellite cells have important support roles for the neurons they surround, it is likely that the marked reduction in the volume of perineuronal sheaths in the extremely advanced age is accompanied by a reduction of those roles, with negative consequences for neuronal activity.

Study Design: The membrane, nucleus, and cytoplasmic contents of satellite cells were evaluated using a transmission electron microscope., Objective: To delineate satellite cell morphometries., Summary of Background Data: The role of the satellite support cells associated with the neuronal cell bodies remains poorly understood. Previous research has identified one type of satellite support cells., Methods: Dorsal root ganglions were excised from 10 adult New Zealand White rabbits. Sections from L2-L5 ganglions were prepared, cut, and analyzed under a transmission electron microscope., Results: A total of 190 neurons and their associated satellite cells were selected for analysis. Three subgroups of satellite cells were identified. The two predominant subgroups consisted of previously described satellite cells. The third subgroup consisted of highly complex and unusual cells. Nineteen satellite cells (4%) did not conform to any previous description of glial cells. Cells were characterized by larger nuclei, with numerous inclusions, and by extensively convoluted reflections of the cellular membrane. These cells were "perched" or "piggy-backed" on top of a convoluted and multilayered cytoplasmic sheet., Conclusion: A new type of support cell representing a different cell line or a highly adapted cell with specific functional capacities was identified.

This study investigated quantitative aspects of the gap junctions between satellite neuroglial cells that envelope the spinal ganglion neurons in rabbits aged 1 year (young), 3.6 years (adult), 6.7 years (old), and 8.8 years (very old). Both the total number of gap junctions present in 30,000 microm2 of surface area occupied by perineuronal satellite cells, and the density of these junctions increased throughout life, including the extremely advanced age. By contrast, the mean length of individual gap junctions did not change with age. Thus, the junctional system which provides morphological support for the metabolic cooperation between satellite cells in rabbit spinal ganglia becomes more extensive as the age of the animal increases. These results support the hypothesis that the gap junctions between perineuronal satellite cells are involved in the spatial buffering of extracellular K+ and in neuroprotection.

Current information indicates that glial cells participate in all the normal and pathological processes of the central nervous system. Although much less is known about satellite glial cells (SGCs) in sensory ganglia, it appears that these cells share many characteristics with their central counterparts. This review presents information that has been accumulated recently on the physiology and pharmacology of SGCs. It appears that SGCs carry receptors for numerous neuroactive agents (e.g., ATP, bradykinin) and can therefore receive signals from other cells and respond to changes in their environment. Activation of SGCs might in turn influence neighboring neurons. Thus SGCs are likely to participate in signal processing and transmission in sensory ganglia. Damage to the axons of sensory ganglia is known to contribute to neuropathic pain. Such damage also affects SGCs, and it can be proposed that these cells have a role in pathological changes in the ganglia.

Varicella-zoster virus (VZV) causes varicella and establishes latency in sensory ganglia. VZV reactivation results in herpes zoster. We developed a model using human dorsal root ganglion (DRG) xenografts in severe combined immunodeficient (SCID) mice to investigate VZV infection of differentiated neurons and satellite cells in vivo. DRG engrafted under the kidney capsule and contained neurons and satellite cells within a typical DRG architecture. VZV clinical isolates infected the neurons within DRG. At 14 days postinfection, VZ virions were detected by electron microscopy in neuronal cell nuclei and cytoplasm but not in satellite cells. The VZV genome copy number was 7.1 x 10(7) to 8.0 x 10(8) copies per 10(5) cells, and infectious virus was recovered. This initial phase of viral replication was followed within 4-8 weeks by a transition to VZV latency, characterized by the absence of infectious virus release, the cessation of virion assembly, and a reduction in VZV genome copies to 3.7 x 10(5) to 4.7 x 10(6) per 10(5) cells. VZV persistence in DRG was achieved without any requirement for VZV-specific adaptive immunity and was associated with continued transcription of the ORF63 regulatory gene. The live attenuated varicella vaccine virus exhibited the same pattern of short-term replication, persistence of viral DNA, and prominent ORF63 transcription as the clinical isolates. VZV-infected T cells transferred virus from the circulation into DRG, suggesting that VZV lymphotropism facilitates its neurotropism. DRG xenografts may be useful for investigating neuropathogenic mechanisms of other human viruses.

The chondroitin sulphate proteoglycan NG2 blocks neurite outgrowth in vitro and thus may be able to inhibit axonal regeneration in the CNS. We have used immunohistochemistry to compare the expression of NG2 in the PNS, where axons regenerate, and the spinal cord, where regeneration fails. NG2 is expressed by satellite cells in dorsal root ganglia (DRG) and in the perineurium and endoneurium of intact sciatic nerves of adult rats. Endoneurial NG2-positive cells were S100-negative. Injury to dorsal roots, ventral rami or sciatic nerves had no effect on NG2 expression in DRG but sciatic nerve section or crush caused an upregulation of NG2 in the damaged nerve. Strongly NG2-positive cells in damaged nerves were S100-negative. The proximal stump of severed nerves was capped by dense NG2, which surrounded bundles of regenerating axons. The distal stump, into which axons regenerated, also contained many NG2-positive/S100-negative cells. Immunoelectron microscopy revealed that most NG2-positive cells in distal stumps had perineurial or fibroblast-like morphologies, with NG2 being concentrated at the poles of the cells in regions exhibiting microvillus-like protrusions or caveolae. Compression and partial transection injuries to the spinal cord also caused an upregulation of NG2, and NG2-positive cells and processes invaded the lesion sites. Transganglionically labelled ascending dorsal column fibres, stimulated to sprout by a conditioning sciatic nerve injury, ended in the borders of lesions among many NG2-positive processes. Thus, NG2 upregulation is a feature of the response to injury in peripheral nerves and in the spinal cord, but it does not appear to limit regeneration in the sciatic nerve.

The gap junctions between perineuronal satellite cells were studied in the spinal ganglia of 12, 42, and 79-month-old rabbits. The mean number of gap junctions per 100 microm2 of surface of the section occupied by satellite cells was significantly greater in old rabbits than young adults. Since the mean length of individual gap junctions did not change with age, the increase in number of gap junctions cannot be due to fragmentation of pre-existing gap junctions but is very likely due to the formation of new gap junctions. The increase in number of gap junctions cannot be related to an increase in number of perineuronal satellite cells since the mean number of these cells is significantly smaller in aged rabbits than in young adults. It is suggested that the increase in number of gap junctions with age may enhance the suggested neuroprotective role of satellite cells towards ganglionic neurons. The present findings, together with previous observations, suggest that the gap junctions between perineuronal satellite cells are dynamic structures, able to adapt to varying neuronal demands and varying environmental conditions.

We studied mitochondria in the satellite cell sheaths which envelope the spinal ganglion neurons of rabbits aged 12, 42, and 79 months. While the mean cytoplasmic volume of satellite cell sheaths did not change significantly with age, the mean percentage of cytoplasmic volume occupied by mitochondria decreased with age. This decrease is mainly due to a reduction in the total mitochondrial mass and only in minor part is a consequence of lipofuscin accumulation. Mitochondrial structure did not change, while mitochondrial size increased with age. Comparison between mitochondria in nerve cell bodies and those in satellite cell sheaths showed that: (1) the mean percentage of cytoplasmic volume occupied by mitochondria was greater in nerve cell bodies than satellite cell sheaths and the ratio between these two percentages remained constant with advancing age; (2) the total mitochondrial mass was much greater in nerve cell bodies than satellite cell sheaths and the ratio between these two values increased with age; (3) the extent of increase of mitochondrial size with age was similar in nerve cell bodies and satellite cell sheaths. The results of the present study suggest that: (1) the ability of satellite cell sheaths to produce energy decreases with age; (2) the decreased ability of sensory neurons in old animals to meet high energy demands may be partly due to the diminished contribution of their associated satellite cell sheaths.

We studied the Golgi apparatus in the satellite cell sheaths enveloping spinal ganglion neurons of rabbits aged 12, 42, and 79 months. We found neither structural changes nor indications of peripheral displacement of this organelle with advancing age. The mean percentage of cytoplasmic volume occupied by the Golgi apparatus decreased significantly passing from young adult to old rabbits. This decrease was only in very minor part a consequence of lipofuscin accumulation, so that the ratio between the total volume of the Golgi apparatus and the functionally active volume of cytoplasm decreased with age. The mean cytoplasmic volume of perineuronal satellite cell sheaths did not change significantly with increasing age, whereas the total volume of the Golgi apparatus within these sheaths decreased significantly with age. This decrease strongly suggests that the activity of satellite cells diminishes in old age, further suggesting that these cells are unable to compensate for the decrease in the neuronal metabolism that a number of authors have described in old age.

This study investigated satellite cell changes in mouse L4 and L5 spinal ganglia 14 days after unilateral transection of sciatic and saphenous nerves. The ganglia were studied under the electron microscope in single and serial sections, and by dye injection. Satellite cell responses to axon injury of the neurons with which they are associated included the formation of bridges connecting previously separate perineuronal sheaths and the formation of new gap junctions, resulting in more extensive cell coupling. Some possible consequences of these satellite cell reactions are briefly discussed.

Perineuriomas (PN) are uncommon, slowly growing, usually benign tumors composed of well-differentiated perineural cells. Two variants are recognized: intraneural perineuriomas and soft tissue perineurioma, which includes a sclerosing subset of tumors. They are usually reported in the adult population. We present three cases of soft tissue perineuriomas in children. One was located in the deep soft tissue of the retroperitoneum in a 14-year-old girl, the second one in the left thumb of a 14-year-old boy, and the third one in the index finger of a 16-year-old boy. This report, which describes the clinicopathologic, immunohistochemical, and ultrastructural features of these tumors, should alert pathologists to the occurrence of perineuriomas in children. A review of the English language literature on perineuriomas in children is also included.

Data on the presence of NGF receptors in the satellite cells of spinal ganglia are scanty and contradictory. In the present study we used immunocytochemistry to examine the distribution of these receptors in spinal ganglia of the adult rat by light and electron microscopy. We found that (1) all satellite cells were immmunoreactive to p75 and the mean density of gold particles (mean number per microm2) was significantly greater in the satellite cell sheath than in the nerve cell body; (2) numerous satellite cells were immunoreactive for trkA with a mean density of gold particles slightly greater in the satellite cell sheath than in the nerve cell body, although the difference was not statistically significant; (3) both p75 and trkA immunoreactivity were confined to the cytoplasm. We suggest that the p75 receptor may be involved in the NGF-induced outgrowth of slender projections from the nerve cell body surface. With regard to the trkA receptor, satellite cells might be supported trophically by NGF released from the neuron with which they are associated; alternatively, satellite cells might internalize NGF to constitute a reservoir for later release to the neuron.

Slender projections, similar to microvilli, are the main specialization of the perikaryal surface of sensory ganglion neurons. The extent of these projections correlates closely with the volume of the corresponding nerve cell body. It is likely that the role of perikaryal projections of sensory ganglion neurons, which lack dendrites, is to maintain the surface-to-volume ratio of the nerve cell body above some critical level for adequate metabolic exchange. Satellite cells probably have the ability to promote, or provide a permissive environment for, the outgrowth of these projections. It is not yet known whether the effect of satellite cells is mediated by molecules associated with their plasma membrane or by diffusible factors. Furthermore, receptor molecules for numerous chemical agonists are located on the nerve cell body surface, but it is not known whether certain molecules are located exclusively on perikaryal projections or are also present on the smooth surface between these projections. Further study of the nerve cell body surface and of the influence that satellite cells exert on it will improve our understanding of the interactions between sensory ganglion neurons and satellite neuroglial cells.

Numerous studies have been done on the effect of nerve injury on neurons of sensory ganglia but little is known about the contribution of satellite glial cells (SCs) in these ganglia to post-injury events. We investigated cell-to-cell coupling and ultrastructure of SCs in mouse dorsal root ganglia after nerve injury (axotomy). Under control conditions SCs were mutually coupled, but mainly to other SCs around a given neuron. After axotomy SCs became extensively coupled to SCs that enveloped other neurons, apparently by gap junctions. Serial section electron microscopy showed that after axotomy SC sheaths enveloping neighboring neurons formed connections with each other. Such connections were absent in control ganglia. The number of gap junctions between SCs increased 6.5-fold after axotomy. We propose that axotomy induces growth of perineuronal SC sheaths, leading to contacts between SCs enveloping adjacent neurons and to formation of new gap junctions between SCs. These changes may be an important mode of glial plasticity and can contribute to neuropathic pain.

Suramin is being used either alone, or in combination with other chemotherapeutic agents, in the treatment of hormone-refractory or metastatic prostate cancer. Use of this potentially valuable chemotherapy is limited by a dose-dependent polyneuropathy. It has been difficult in human studies to characterize peripheral suramin toxicity separately from cancer-related neuropathy. To characterize suramin-induced neuropathy in a rat model, adult rats were given either a single dose of 500 mg/kg (high dose) or 50 mg/kg (low dose) weekly suramin for 2 months. Electrophysiology and peroneal/sural nerve morphometry were performed. In high dose animals, neuropathy developed within 2 weeks, most severe in the digital sensory responses (DSR) (p<0.05) and tail and hind limb compound muscle action potential (p<0.001). Histologically, there was evidence of axonal degeneration and axon atrophy. With low dose suramin, the DSR (p<0.05) and tail distal sensory and motor responses (p<0.01) were most severely affected at 2 months. Axonal degeneration was seen in teased fibers from most animals. With TEM, there were abundant characteristic lysosomal inclusion bodies in DRG and Schwann cells. Electrophysiological and histological evidence of peripheral demyelination was rare, being observed in only one animal. Suramin induced a length, dose and time-dependent axonal sensorimotor polyneuropathy associated with axonal degeneration, atrophy, and accumulation of glycolipid lysosomal inclusions.

Patients with a peripheral nerve injury often suffer from persistent chronic pain, but the underlying mechanism remains largely unknown. The persistent nature of the pain suggests injury-induced profound structural changes along the sensory pathways. In the present study, using the plant Griffonia simplicifolia I isolectin B4 (IB4) as a marker for nonpeptidergic small sensory neurons, we sought to examine whether these neurons sprout in the dorsal root ganglia (DRG) in response to peripheral nerve injury. The lumbar 5 (L5) spinal nerve was transected, and rats were allowed to survive for varying lengths of time before IB4 histology was performed. We found that a subpopulation of IB4-positive sensory neurons sprouted robustly after spinal nerve injury. Twelve weeks after spinal nerve injury, the IB4-positive ring structures became dramatic and encircled both large and small neurons in the DRG. The aberrant sprouting of small sensory neurons was also demonstrated by retrograde labeling. The processes of satellite cells surrounding large sensory neurons also became IB4 positive, and 87.8% of perineuronal IB4-positive ring structures intermingled and/or coexpressed with glial fibrillary acidic protein-positive satellite cells. Thus, the sprouting axons of IB4-positive neurons were intermingled with IB4-positive satellite cells, forming perineuronal ring structures surrounding large-diameter neurons. Ultrastructural examinations further confirmed that IB4-positive nerve terminals were entangled with satellite cells and IB4-negative unmyelinated sprouting fibers around sensory neurons. These studies have provided the first evidence that a subpopulation of IB4-binding small sensory neurons sprouts and forms perineuronal ring structures together with IB4-positive satellite cells in response to nerve injury. The significance of the sprouting of IB4-positive neurons remains to be determined., (Copyright 2001 Wiley-Liss, Inc.)

The mechanisms governing the regeneration of denervated peripheral mechanoreceptors are similar to those of peripheral nerves. The ability to regenerate depends partly on changes of the Schwann cell phenotype. The transforming growth factor beta (TGF-beta) family have been implicated in induction of Schwann cell proliferation, production of extracellular matrix and neurotrophin synthesis as well as synthesis or repression of cell adhesion molecules. Hence, they may prove to be of importance for regenerative mechanisms in peripheral mechanoreceptors. The distribution of TGF-beta, the receptors I and II and intra-cellular second messengers, Smad 2/3 and 4 was assessed in sensory neurones, peripheral nerves and mechanoreceptors by immuno-histochemistry, immuno-electron microscopy and in situ hybridisation. TGF-beta2 mRNA and TGF-beta2-like immunoreactivity (IR) were expressed in injured small and medium sized rat sensory neurones of dorsal root ganglia. TGF-beta and receptor II mRNA and immunoreactivities (IR) were present in satellite cells. Intact and injured sensory neurones expressed receptor I mRNA and Smad 2 mRNA. TGF-beta2 mRNA was found in transected nerve stumps and in sensory mechanoreceptors. TGF-beta1, 2 and Smad 4 were also observed in inner core lamellar cells of intact and denervated cat Pacinian corpuscles. Lamellar cells of intact and denervated Meissner corpuscles were TGF-beta immunoreactive. Merkel cells were receptors I and II immunoreactive. In conclusion, cutaneous and subcutaneous mechanoreceptors differ with regard to the expression of TGF-beta isoforms and receptors.

This study presents the first direct evidence for herpes simplex virus type 1 (HSV-1) infection in the neurons of the vestibular ganglion. Although many investigators have reported electron microscopic evidence of HSV-1 infection in sensory ganglia, HSV-1 infection in the vestibular ganglion has not been described. Vestibular ganglion neurons have a unique structure, with a loose myelin sheath instead of the satellite cell sheath that is seen in other ganglia. This loose myelin is slightly different from compact myelin which is known as too tight for HSV-1 to penetrate. The role of loose myelin in terms of HSV-1 infection is completely unknown. Therefore, in an attempt to evaluate the role of loose myelin in HSV-1 infection, we looked for HSV-1 particles, or any effects mediated by HSV-1, in the vestibular ganglion as compared with the geniculate ganglion. At the light microscopic level, some neurons with vacuolar changes were observed, mainly in the distal portion of the vestibular ganglion where the communicating branch from the geniculate ganglion enters. At the electron microscopic level, vacuoles, dilated rough endoplasmic reticulum and Golgi vesicles occupied by virus were observed in both ganglia neurons. In contrast, viral infections in Schwann and satellite cells were observed only in the geniculate ganglion, but not in the vestibular ganglion. These results suggest that loose myelin is an important barrier to HSV-1 infection, and it must play an important role in the prevention of viral spread from infected neurons to other cells.