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PubMed2003

Sex-related difference in collateral sprouting of nociceptive axons after peripheral nerve injury in the rat.

Possible sex-related differences in the extent of collateral sprouting of noninjured nociceptive axons after peripheral nerve injury were examined. In the first experiment, peroneal, tibial, and saphenous nerves were transected and ligated in female and male rats. Eight weeks after nerve injury, skin pinch tests revealed that the nociceptive area of the noninjured sural nerve in the instep skin expanded faster in females; the final result was a 30% larger increase in females than in males. In the second experiment, the end-to-side nerve anastomosis was used as a model for axon sprouting. In addition to the previous procedure, the end of an excised peroneal nerve segment was sutured to the side of the intact sural nerve. Eight weeks later, collateral sprouting of nociceptive axons into the anastomosed peroneal nerve segment was assessed by the nerve pinch test and axon counting. There was no significant difference with respect to the percentages of male and female rats with a positive nerve pinch test. The number of myelinated axons in the anastomosed nerve segment was significantly larger in female (456 +/- 217) than in male (202 +/- 150) rats, but the numbers of unmyelinated axons were not significantly different. In normal sural nerves, the numbers of either all myelinated axons or thin myelinated axons did not significantly differ between the two sexes. Therefore, the more extensive collateral axon sprouting observed in female than in male rats is probably due to the higher sprouting capacity of thin myelinated sensory axons in females.

Animals↗
PubMed1999

Axonal degeneration in the pathogenesis of multiple sclerosis.

Axonal degeneration plays an important role in the accumulation of disability in patients with multiple sclerosis (MS). Pathological studies have demonstrated axonal damage, particularly in areas of acute inflammation and demyelination, and in chronic lesions. Axonal loss and its progression, which is associated with neurological disability, has also been demonstrated by magnetic resonance imaging (MRI) studies. The mechanisms of axonal loss are uncertain, but may involve axonal degeneration secondary to demyelination, or damage to the axonal cytoskeleton. Inflammatory mediators, including cytokines and proteolytic enzymes may contribute to axonal damage, as may nitric oxide. Axonal destruction may also be due to immune attack directed at axonal components. The realisation that axonal degeneration is a fundamental component of MS that may occur early in the disease course should alter the approach to management and open avenues to a more targeted immunotherapy aimed at reducing the progression of disability.

Axons↗
PubMed2003

Spatial requirements for TrkA kinase activity in the support of neuronal survival and axon growth in rat sympathetic neurons.

Nerve growth factor (NGF) interacts with its receptor tyrosine kinase, TrkA, at axon terminals to produce local signals within axon terminals and retrograde signals to the neuronal cell body. According to prevalent theory, retrograde signaling requires the retrograde transport to the cell bodies of signaling endosomes containing activated TrkA complexed with NGF. Alternative mechanisms in which retrograde signals reach the cell bodies unaccompanied by NGF may or may not require activated TrkA in the cell body. To help distinguish this possibility, we investigated the spatial requirements of TrkA kinase activity for neuronal survival and axon growth in rat sympathetic neurons supported by NGF provided only to distal axons. Inhibition of local TrkA kinase activity in the distal axons by K252a blocked local axon growth and induced apoptosis. Although local application of K252a to cell bodies/proximal axons resulted in a sustained loss of phosphorylated TrkA from the cell bodies/proximal axons, the neurons survived, and growth of the distal axons was not inhibited. These results suggest that TrkA kinase activity in distal axons, but not in the cell bodies, is required for both local growth and retrograde survival signaling. These results support the hypothesis that retrograde signals can be carried by mechanisms downstream of TrkA activity.

Animals↗
PubMed1996

Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system.

During nervous system development, spinal commissural axons project toward floor plate cells and trochlear motor axons extend away from these cells. Netrin-1, a diffusible protein made by floor plate cells, can attract spinal commissural axons and repel trochlear axons in vitro, but its role in vivo is unknown. Netrin-1 deficient mice exhibit defects in spinal commissural axon projections that are consistent with netrin-1 guiding these axons. Defects in several forebrain commissures are also observed, suggesting additional guidance roles for netrin-1. Trochlear axon projections are largely normal, predicting the existence of additional cues for these axons, and evidence is provided for a distinct trochlear axon chemorepellent produced by floor plate cells. These results establish netrin-1 as a guidance cue that likely collaborates with other diffusible cues to guide axons in vivo.

Alleles↗
PubMedDate not supplied

Injury-related dynamic myelin/oligodendrocyte axon-outgrowth inhibition in the central nervous system.

CONTEXT: By contrast with the glial scar, myelin was considered a constitutive static inhibitory barrier unreactive to lesions in the central nervous system (CNS). However, recent results suggest considerable add-on inhibition of myelin as a result of CNS injury. Furthermore, catastrophic events cause morphological and biochemical changes in the axon itself. This results in the accumulation of cytoskeleton components and intraaxonal transported proteins paralleled by extensive membrane remodelling at the axonal tip (a process called axotomy) which might modify the axonal response to its inhibitory environment. STARTING POINT: Ji-Eun Kim and colleagues recently reported an axonal subpopulation with a different capacity to respond to myelin inhibitors (Neuron 2004; 44: 439-51). Axonal specificity but also evidence for injury reactivity summarised here challenges our understanding of axon-growth inhibition in the injured CNS. This might be due to (i) qualitative and quantitative enrichment of the periaxonal environment by myelin/oligodendrocytes, (ii) increased axonal sensitivity to its inhibitory environment, and (iii) axons and lesion-induced, altered axonal signalling. WHERE NEXT? Postlesional reactive inhibition of myelin or the oligodendrocyte necessitates the development of novel screening approaches and therapeutic agents to promote axonal regeneration. Moreover, we need to improve our understanding of the pathophysiology of the lesion to find more efficient experimental strategies to restore neurological function.

Animals↗
PubMed1997

Sex differences in the development of axon number in the splenium of the rat corpus callosum from postnatal day 15 through 60.

Axon number in the splenium was examined at 15, 25 and 60 days of age in male and female rats. The splenium (posterior fifth) of the corpus callosum was found to contain the axons from the visual cortex at all three ages and was extensively sampled with electron microscopy. Overall, there was a 15% decrease in the total number of axons between postnatal day 15 and day 60 in both sexes. The observed decrease in axon number between day 15 and 25 in both males and females is consistent with Elberger's (A.J. Elberger, Transitory corpus callosum axons projecting throughout developing rat visual cortex revealed by DiI, Cereb. Cortex 4 (1994) 279-299) data which suggest that the pattern of visual callosal projections in the rat visual cortex is not restricted to the adult form until the fourth postnatal week. There was a further decrease in axon number between day 25 and day 60 in females only such that by 60 days of age, the total number of axons was equivalent between the sexes. Thus in the rat splenium, males appear to attain the adult number of axons earlier than females. These results also indicate that there is a sex difference in the timing of axon withdrawal in the rat splenium, with axon withdrawal continuing in females after it has ceased in males.

Animals↗
PubMed1999

Electrically mediated regeneration and guidance of adult mammalian spinal axons into polymeric channels.

An extracellular electric field has been shown to influence the regeneration of nerve fibers within the adult mammalian spinal cord. However, in these studies, few axons were labeled by local application of intracellular markers relative to the number of axons transected. This has limited an evaluation of the robustness of the response, and the direction of growth of regenerating axons that might be influenced by the orientation of the applied voltage gradient. In this study, a hollow silicone rubber tube (c. 6 mm x 1 mm outside diameter) containing a cathodal (negative) electrode was inserted longitudinally into the dorsal half of the adult guinea-pig spinal cord. The electric field ( approximately 100 microV/mm) was imposed within the damaged spinal cord with an implanted d.c. stimulator for about three weeks. Based on previous studies, this orientation of the electric field would be expected to both initiate axonal regeneration and guide growing axons to, and into, the silicone guidance channel. In experimental animals (n = 20), a robust regeneration of axons into the tube was observed in more than half the cases. These axons were traced from surrounding white and gray matter by anterograde and retrograde labeling using a tetramethylrhodamine-conjugated dextran as an intracellular marker. Control animals (n = 16) received tubes with inactive electrodes. It was rare to find any axons within control guidance channels, since adult mammalian central nervous system axons do not regenerate. This report provides evidence for not only the facilitated regeneration of adult mammalian central axons, but also their guidance, by an imposed electric field.

Animals↗
PubMed1999

Direct innervation of identified tectothalamic neurons in the inferior colliculus by axons from the cochlear nucleus.

The present study sought to identify tectothalamic neurons in the rat inferior colliculus that receive their innervation directly from the cochlear nuclei and to identify the axons that provide the innervation. A direct projection would bypass the binaural interactions of the superior olivary complex and provide the quickest route to the neocortex. Axons, primarily from the dorsal cochlear nucleus, were labeled with anterograde transport of dextran and terminated in the central nucleus of the inferior colliculus in a laminar pattern. Most labeled axons were thin and simply branched. Other axons were thicker, gnarly, less frequently observed and probably originated from the ventral cochlear nucleus. None had concentrated endbulbs or a nest of endings. Both types of axons terminated primarily in the central nucleus and layer 3 of the external cortex. This pattern suggests that the combination of these subdivisions in the rat are equivalent to the central nucleus as defined in other species. Tectothalamic neurons in the inferior colliculus in the same animals were identified by retrograde transport from the medial geniculate body and intracellular injection of Lucifer Yellow. A number of different cell types act as tectothalamic neurons and receive contacts from cochlear nucleus axons. These include flat cells (disc-shaped), less-flat cells and stellate cells. Two innervation patterns were seen: a combination of axosomatic and axodendritic contacts, and predominantly axodendritic contacts. Both patterns were seen in the central nucleus, but axosomatic contacts were seen less often in the other subdivisions. This is the first study to show direct connections between cochlear nuclear axons and identified tectothalamic neurons. The layers of axons from cochlear nuclei may provide convergent inputs to neurons in the inferior colliculus rather than the heavy inputs from single axons typical of lower auditory nuclei. Excitatory synapses made by axons from the cochlear nuclei on tectothalamic neurons may provide a substrate for rapid transmission of monaural information to the medial geniculate body.

Animals↗
PubMed2003

Rac proteins and the control of axon development.

Rac GTPases and their effectors control cellular morphogenesis in a wide range of developmental contexts by regulating the structure and dynamics of the actin cytoskeleton. Although much is known about the biochemistry of Racs and Rac regulators, less is known about how Racs control cellular morphogenesis, including axon development, in vivo. Recent loss-of-function genetic studies using model organisms have shown that Racs and their effectors are required for multiple aspects of axon development, including axon outgrowth, axon guidance and axon branching. Interestingly, these studies have also revealed that Rac activity is required to prune spurious axons and branches. Analyses of Racs and their upstream and downstream effectors suggest that Rac signaling is complex. Different neurons utilize distinct combinations of upstream Rac regulators during axon development, possibly reflecting responses to different axon path-finding signals, and Racs use distinct downstream effectors to mediate different aspects of axon development, possibly reflecting differential regulation of the lamellipodial and filopodial growth-cone actin-cytoskeleton domains underlying axon developmental events.

Animals↗
PubMed2003

Distribution of GAP-43, beta-III tubulin and F-actin in developing and regenerating axons and their growth cones in vitro, following neurotrophin treatment.

Brain derived neurotrophic factor (BDNF) when added to explant cultures of both embryonic and adult retinal ganglion cell (RGC) axons exerted a marked effect on their growth cone size and complexity and also on the intensity of GAP-43, beta-III tubulin and F-actin immunoreaction product in their axons. GAP-43 was distributed in axons, lamellipodia, and filopodia whereas beta-III tubulin was distributed along the length of developing and adult regenerating axons and also in the C-domain of their growth cones. BDNF-treated developing RGC growth cones were larger and displayed increased numbers of GAP-43 and microtubule-containing branches. Although filopodia and lamellipodia were lost from both developing and adult RGC growth cones following trkB-IgG treatment, the intensity of the immunoreaction product of all these molecules was reduced and trkB-IgGs had no effect on the axonal distribution of betas-III tubulin and GAP-43. BDNF-treated growth cones also displayed increased numbers of F-actin containing filopodia and axonal protrusions. This study demonstrates, for the first time, that trkB-IgG treatment causes the loss of F-actin in the P-domain of growth cone tips in developing and regenerating RGC axons. Although microtubules and F-actin domains normally remained distinct in cultured growth cones, beta-III tubulin and F-actin overlapped within the growth cone C-domain, and within axonal protrusions of adult RGC axons, under higher concentrations of BDNF. The collapse of RGC growth cones appeared to correlate with the loss of F-actin. In vitro, trkB signalling may therefore be involved in the maintenance and stabilisation of RGC axons, by influencing F-actin polymerisation, stabilisation and distribution.

Actin Cytoskeleton↗
PubMed1998

A strong myelin thickness-axon size correlation emerges in developing nerves despite independent growth of both parameters.

The axon determines whether or not it is myelinated by the Schwann cell. At maturity there is a positive correlation between sheath thickness and axon calibre. This correlation is initially very low or absent, but gradually strengthens during development. This increase could come about because the axon continuously controls Schwann cell myelinating activity, so that a given axon calibre is associated with a particular myelin sheath thickness, an interaction which would entail the Schwann cell continuously monitoring and responding to axon size. This seems unnecessarily complex. This theoretical study shows that the strong correlation between the 2 parameters within a given myelinated fibre population may come about in a much simpler way than outlined above. This is demonstrated by modelling the growth and myelination of a hypothetical population, utilising data from earlier studies on cervical ventral motoneuron axon development. The hypothesis tested shows that the only instructive interactions by the axon on the Schwann cell necessary for the strong correlation between the 2 parameters to emerge are for the initiation of myelination, its continuation and its termination. These could result from a single stimulus being switched on, persisting for a time and being switched off. Under this influence, the Schwann cell is assumed to proceed to form the myelin sheath at a constant rate which it itself inherently determines, in the absence of any quantitative influence exerted by the axon. This continues until the stimulus for myelination ceases to emanate from the axon. The validity of the hypothesis is demonstrated, because the resulting myelin-axon relationships correspond closely to those observed during development.

Animals↗
PubMed1994

Calcium-mediated degeneration of the axonal cytoskeleton in the Ola mouse.

The C57BL/Ola (Ola) mouse is a mutant substrain in which transected axons undergo very slow Wallerian degeneration. Because axonal degradation during Wallerian degeneration is calcium dependent, we tested whether Ola axons are susceptible to calcium-mediated axonal degeneration by comparing neurofilament degradation between Ola and C57BL/6 mice in sciatic nerve explants. Using immunoblot analysis of neurofilament degradation and electron microscopy we found that as in normal axons, axonal degeneration in the Ola is calcium dependent. However, when compared with normal animals, higher levels of calcium were required for complete degradation of neurofilaments in Ola nerve, suggesting a relative insensitivity to calcium-mediated degeneration in the Ola. We conclude that calcium-activated proteases are present and active in Ola axons but that higher levels of calcium are required to accomplish complete axonal degradation. These results suggest a possible mechanism for prolonged survival of transected Ola axons and provide potential insight into the pathophysiology of axonal degeneration in injury and disease.

Animals↗
PubMed1997

Intracellular concentrations of major ions in rat myelinated axons and glia: calculations based on electron probe X-ray microanalyses.

Electron probe x-ray microanalysis (EPMA) was used to measure water content (percent water) and dry weight elemental concentrations (in millimoles per kilogram) of Na, K, Cl, and Ca in axoplasm and mitochondria of rat optic and tibial nerve myelinated axons. Myelin and cytoplasm of glial cells were also analyzed. Each anatomical compartment exhibited characteristic water contents and distributions of dry weight elements, which were used to calculate respective ionized concentrations. Free axoplasmic [K+] ranged from approximately 155 mM in large PNS and CNS axons to approximately 120-130 mM in smaller fibers. Free [Na+] was approximately 15-17 mM in larger fibers compared with 20-25 mM in smaller axons, whereas free [Cl-] was found to be 30-55 mM in all axons. Because intracellular Ca is largely bound, ionized concentrations were not estimated. However, calculations of total (free plus bound) aqueous concentrations of this element showed that axoplasm of large CNS and PNS axons contained approximately 0.7 mM Ca, whereas small fibers contained 0.1-0.2 mM. Calculated ionic equilibrium potentials were as follows (in mV): in large CNS and PNS axons, E(K) = -105, E(Na) = 60, and E(Cl) = -28; in Schwann cells, E(K) = -107, E(Na) = 33, and E(Cl) = -33; and in CNS glia, E(K) = -99, E(Na) = 36, and E(Cl) = -44. Calculated resting membrane potentials were as follows (in mV, including the contribution of the Na+,K+-ATPase): large axons, about -80; small axons, about -72 to -78; and CNS glia, -91. E(Cl) is more positive than resting membrane potential in PNS and CNS axons and glia, indicating active accumulation. Direct EPMA measurement of elemental concentrations and subsequent calculation of ionized fractions in axons and glia offer fundamental neurophysiological information that has been previously unattainable.

Animals↗
PubMed2004

Axonal transport of human alpha-synuclein slows with aging but is not affected by familial Parkinson's disease-linked mutations.

Biochemical and genetic abnormalities of alpha-synuclein (alpha-Syn) are implicated in the pathogenesis of Parkinson's disease (PD) and other alpha-synucleinopathies. The abnormal intraneuronal accumulations of alpha-Syn in Lewy bodies (LBs) and Lewy neurites (LNs) have implicated defects in axonal transport of alpha-Syn in the alpha-synucleinopathies. Using human (Hu) alpha-Syn transgenic (Tg) mice, we have examined whether familial PD (FPD)-linked mutations (A30P and A53T) alter axonal transport of Hualpha-Syn. Our studies using peripheral nerves show that Hualpha-Syn and Moalpha-Syn are almost exclusively transported in the slow component (SC) of axonal transport and that the FPD-linked alpha-Syn mutations do not have obvious effects on the axonal transport of alpha-Syn. Moreover, older pre-symptomatic A53T Hualpha-Syn Tg mice do not show gross alterations in the axonal transport of alpha-Syn and other proteins in the SC, indicating that the early stages of alpha-synucleinopathy in A53T alpha-Syn Tg mice are not associated with gross alterations in the slow axonal transport. However, the axonal transport of alpha-Syn slows significantly with aging. Because the rate of axonal transport affects the stability and accumulation of proteins in axons, age-dependent-slowing alpha-Syn is a likely contributor to axonal aggregation of alpha-Syn in alpha-synucleinopathy.

Aging↗
PubMed2005

Growth-associated protein GAP-43 and L1 act synergistically to promote regenerative growth of Purkinje cell axons in vivo.

Neuronal expression of growth-associated protein 43 (GAP-43) and the cell adhesion molecule L1 has been correlated with CNS axonal growth and regeneration, but it is not known whether expression of these molecules is necessary for axonal regeneration to occur. We have taken advantage of the fact that Purkinje cells do not express GAP-43 or L1 in adult mammals or regenerate axons into peripheral nerve grafts to test the importance of these molecules for axonal regeneration in vivo. Transgenic mice were generated in which Purkinje cells constitutively express L1 or both L1 and GAP-43 under the Purkinje cell-specific L7 promoter, and regeneration of Purkinje cell axons into peripheral nerve grafts implanted into the cerebellum was examined. Purkinje cells expressing GAP-43 or L1 showed minor enhancement of axonal sprouting. Purkinje cells expressing both GAP-43 and L1 showed more extensive axonal sprouting and axonal growth into the proximal portion of the graft. When a predegenerated nerve graft was implanted into double-transgenic mice, penetration of the graft by Purkinje cell axonal sprouts was strongly enhanced, and some axons grew along the entire intracerebral length of the graft (2.5-3.0 mm) and persisted for several months. The results demonstrate that GAP-43 and L1 coexpressed in Purkinje cells can act synergistically to switch these regeneration-incompetent CNS neurons into a regeneration-competent phenotype and show that coexpression of these molecules is a key regulator of the regenerative ability of intrinsic CNS neurons in vivo.

Animals↗
PubMed2002

General and variable features of varicosity spacing along unmyelinated axons in the hippocampus and cerebellum.

Along unmyelinated central axons, synapses occur at focal swellings called axonal varicosities (boutons). The mechanisms regulating how frequently synapses and varicosities occur along axons remain poorly understood. Here, to investigate varicosity distribution patterns and the extent to which they may be conserved across different axons, we analyzed varicosity numbers and positions along fluorescently labeled axon branches in hippocampal area CA1 (CA3-to-CA1 "Schaffer collateral" axons) and five other synaptic regions of rat hippocampus and cerebellum. Varicosity spacing varied by region; e.g., 3.7 +/- 0.6 microm (mean +/- SD) for CA3-to-CA1 axons and 5.2 +/- 1.0 microm for cerebellar parallel fibers. Surprisingly, when 56 axons from these different regions were pooled into a single heterogeneous group, a general relationship emerged: the spacing variability (SD) was a constant fraction of the mean spacing, suggesting that varicosities along different axons are distributed in a fundamentally similar, scaled manner. Varicosity spacing was neither regular nor random but followed a pattern consistent with random synaptic distributions and the occurrence of multiple-synapse boutons. A quantitative model reproduced the salient features of the data and distinguished between two proposed mechanisms relating axonal morphogenesis and synaptogenesis.

Animals↗
PubMed1997

Calpain activity promotes the sealing of severed giant axons.

A barrier (seal) must form at the cut ends of a severed axon if a neuron is to survive and eventually regenerate. Following severance of crayfish medial giant axons in physiological saline, vesicles accumulate at the cut end and form a barrier (seal) to ion and dye diffusion. In contrast, squid giant axons do not seal, even though injury-induced vesicles form after axonal transection and accumulate at cut axonal ends. Neither axon seals in Ca2+-free salines. The addition of calpain to the bath saline induces the sealing of squid giant axons, whereas the addition of inhibitors of calpain activity inhibits the sealing of crayfish medial giant axons. These complementary effects involving calpain in two different axons suggest that endogenous calpain activity promotes plasmalemmal repair by vesicles or other membranes which form a plug or a continuous membrane barrier to seal cut axonal ends.

Animals↗
PubMed1995

A regulatory role for sphingolipids in neuronal growth. Inhibition of sphingolipid synthesis and degradation have opposite effects on axonal branching.

Sphingolipids, particularly gangliosides, are enriched in neuronal membranes where they have been implicated as mediators of various regulatory events. We recently provided evidence that sphingolipid synthesis is necessary to maintain neuronal growth by demonstrating that in hippocampal neurons, inhibition of ceramide synthesis by Fumonisin B1 (FB1) disrupted axonal outgrowth (Harel, R. and Futerman, A. H. (1993) J. Biol. Chem. 268, 14476-14481). We now analyze further the relationship between neuronal growth and sphingolipid metabolism by examining the effect of an inhibitor of glucosylceramide synthesis, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1- propanol (PDMP) and by examining the effects of both FB1 and PDMP at various stages of neuronal development. No effects of FB1 or PDMP were observed during the first 2 days in culture, but by day 3 axonal morphology was significantly altered, irrespective of the time of addition of the inhibitors to the cultures. Cells incubated with FB1 or PDMP had a shorter axon plexus and less axonal branches. FB1 appeared to cause a retraction of axonal branches between days 2 and 3, although long term incubation had no apparent effect on neuronal morphology or on the segregation of axonal or dendritic proteins. In contrast, incubation of neurons with conduritol B-epoxide, an inhibitor of glucosylceramide degradation, caused an increase in the number of axonal branches and a corresponding increase in the length of the axon plexus. A direct correlation was observed between the number of axonal branch points per cell and the extent of inhibition of either sphingolipid synthesis or degradation. These results suggest that sphingolipids play an important role in the formation or stabilization of axonal branches.

Animals↗