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PubMed1985

Axonal transport of the voltage-dependent Na+ channel protein identified by its tetrodotoxin binding site in rat sciatic nerves.

Na+ channels levels were measured in different segments of rat vagus and sciatic nerves by in vitro binding using a tritiated ethylene-diamine tetrodotoxin derivative ([3H]en-TTX). Binding sites were found to accumulate on both sides of a ligature tied on the sciatic nerve indicating an anterograde and retrograde axoplasmic transport of Na+ channels. Accumulation of Na+ channels at the ligature was time-dependent and appeared to occur through fast axoplasmic transport mechanisms. This accumulation on both sides of a ligature was also visualized by autoradiographic studies in longitudinal sections of sciatic nerves using [3H]en-TTX.

Animals↗
PubMed2000

Glutamate and aspartate immunoreactivity in dorsal root ganglion cells supplying visceral and somatic targets and evidence for peripheral axonal transport.

Glutamate (Glu) is released by primary sensory neurons at their central synapses, although immunohistochemical studies have shown that only a proportion of these cell bodies are Glu-immunoreactive. Antisera raised against Glu or aspartate (Asp) were used to investigate whether neurons that store high levels of these substances have a unique neuropeptide content or target projection. In male rats, many lumbar and sacral dorsal root ganglion cells and their associated glia show high levels of Glu or Asp immunoreactivity, and fewer than half of these also express substance P or calcitonin gene-related peptide. Conversely, only a minority of peptide-containing neurons store high levels of excitatory amino acids. When neurons that were labelled retrogradely from somatic (skin, gastrocnemius muscle) or visceral (bladder, rectum) targets were immunostained for peptides or amino acids, there was some variation in the peptide expression of their sensory nerve supply, but there was very little or no difference in the prevalence of Glu- or Asp-immunoreactive neurons. In vitro studies on isolated lumbar dorsal root ganglia showed that, after crushing nerve roots, Glu and Asp were transported in both central and peripheral directions, similar to substance P. These studies showed that primary afferent neurons store different levels of Glu and Asp in their somata but that this is not correlated with their target tissue or peptide content. This suggests that both visceral and somatic sensory neurons may vary considerably in the way they release, store, or metabolise amino acids. Peripheral and central transport of amino acids suggests that, in some neurons, reuptake at the synapse may need to be supplemented by amino acids that are produced or accumulated in the soma.

Animals↗
PubMed1979

Midbrain projections to the trigeminal, facial and hypoglossal nuclei in the opossum. A study using axonal transport techniques.

It has been proposed (see Berntson and Micco for review) that circuits intrinsic to the midbrain play an important role in the elaboration and control of behaviors involving the motor nuclei of the trigeminal, facial and hypoglossal nerves (e.g. defense, threat, attack); but because of technical problems, it has been difficult to analyze their organization. Using the horseradish peroxidase technique we have localized those midbrain neurons which project to each of the above nuclei and by using the autoradiographic method we have plotted the intranuclear distribution of their axons. Using both techniques, we have seen that mesencephalic projections to oral-facial motor nuclei strongly favor the nucleus of the facial nerve. Cells ventral to the cerebral aqueduct, including the ventral periaqueductal gray, the interstitial nucleus of Cajal, the nucleus of Darkshchewitsch and the rostral oculomotor nucleus provide major midbrain-facial projections in the opossum. Their axons terminate densely and bilaterally within areas innervating auricular muscles and to a lesser extent, the platysma sheet. The projection to the caudal auricular area of the facial complex is particularly dense. Neurons within and dorsal to the red nucleus project to regions of the contralateral facial nucleus reported to supply buccolabial, zygomatic and cervical musculature. There is also a minor tectal projection to the facial nucleus. Direct projections to the hypoglossal nuclei also arise within the periaqueductal gray and interstitial nucleus, but if such regions influence the motor trigeminal nucleus, it is mainly by way of dendrites that extend outside the nucleus or by at least one synaptic delay. The mesencephalic nucleus of the trigeminal nerve, however, projects strongly to the motor trigeminal nucleus. These data are discussed in light of their possible functional significance.

Animals↗
PubMed1984

Analysis of the apparent biphasic axonal transport kinetics of fucosylated glycoproteins.

Following intraocular injection of [3H]fucose, which labels many glycoproteins of retinal ganglion cells, the accumulation of transported radioactivity arriving at the superior colliculus (nerve terminals) peaks within a few hours and decays with a time course of hours. Then, over a period of several days, radioactivity again accumulates at the superior colliculus and then decays with a half-life of days. The second peak also represents fast transported material since it occurs almost simultaneously along the optic nerve and tract as well as at the nerve endings. Such data have been interpreted as evidence for both a group of rapidly released, rapidly transported glycoproteins (first peak) and a group of slowly released but rapidly transported glycoproteins (second peak). We investigated this supposition by studying in more detail the metabolism of some individual fucosylated proteins in both the retina and superior colliculus. We noted that much of the radioactivity incorporated in fucosylated glycoproteins at the retina was rapidly metabolized (with a turnover on the order of hours), while the remainder of the fucosylated moieties had a metabolic half-life on the order of days. This was also true of the metabolic behavior of several individual glycoproteins, selected for study because they are major components of the group committed to transport and accumulating in two waves at the superior colliculus. In other experiments we injected [35S]methionine intraocularly and examined the metabolism in the retina and the kinetics of transport to the superior colliculus of the peptide backbone of these same individual proteins. In contrast to the two waves of accumulation of radioactivity from [3H]fucose, accumulation of radioactivity of the peptide backbone of the same glycoproteins was monophasic. Our explanation of these data involves the presence of two types of fucose moieties on the peptides. One group of fucose moieties is labile and is lost from the peptide backbone over a period of hours. Other fucose moieties are approximately as metabolically stable as the peptide backbones to which they are attached. The actual peptide backbones of the glycoproteins are committed to rapid transport over a period of several days. Thus, the first (and most prominent) peak of transported radioactivity in [3H]fucosylated glycoproteins does not represent a discrete phase of transport but, rather, is the summation of kinetics of gradual arrival of proteins and the rapid drop in their specific radioactivity as the more labile moieties of [3H]fucose are lost.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2006

Axonal transport of BDNF precursor in primary sensory neurons.

Recent studies have shown that the precursor of brain-derived neurotrophic factor (pro-BDNF) activates p75NTR with high affinity to induce apoptosis. Here we show that pro-BDNF is transported anterogradely and retrogradely in sensory neurons of adult rats. After a crush injury of sciatic nerves, dorsal roots or dorsal column in adult Sprague-Dawley rats, the immunoreactivity for pro-BDNF accumulated at both the proximal and distal segments. The accumulation reached a maximum at 24 h after injury. Western blot analysis also revealed pro-BDNF in sciatic nerve segments proximal and distal to the ligature and in the spinal cord. Biotinylated or Alexa-488-labelled pro-BDNF injected into sciatic nerve was internalized and transported both retrogradely and anterogradely within sensory neurons. These results demonstrate that pro-BDNF is anterogradely and retrogradely transported in sensory neurons, suggesting that endogenous pro-BDNF may be released and play important functions.

Animals↗
PubMed1983

Axonal transport of beta-adrenergic receptors. Antero- and retrogradely transported receptors differ in agonist affinity and nucleotide sensitivity.

Beta-receptors were measured in longitudinal sections of ligated rat sciatic nerve by autoradiographic localization of 125I-labeled cyanopindolol binding sites. Receptors accumulated at the ligature, both proximally and distally, in a time-dependent fashion. Receptor transport also occurred in an isolated segment of nerve (i.e., a doubly ligated nerve), suggesting that the movement is by fast transport. Pharmacological analysis of the accumulating binding sites indicates that they are beta 2-adrenergic receptors. In competition studies, agonists were 10-30 times more potent on receptors accumulating proximal to the ligature than on distally accumulating receptors, whereas antagonists were equipotent on both. Guanyl-5'-yl-imidodiphosphate (GppNHp) decreased the potency of agonists at proximal receptors in a dose-dependent fashion. Distal receptors were much less sensitive to GppNHp. Other nucleotides displayed varying abilities to mimic the effect of GppNHp, suggesting the involvement of a guanine nucleotide-binding protein in regulating agonist affinity. Thus, presynaptic beta 2-adrenergic receptors were identified in rat sciatic nerve. A small fraction of them apparently moves by fast transport. The anterogradely transported receptors have binding properties which differ from the retrogradely moving receptor and appear to be in functional association with a nucleotide regulatory protein.

Adrenergic beta-Agonists↗
PubMed2000

Retrograde axonal transport of BDNF in retinal ganglion cells is blocked by acute IOP elevation in rats.

PURPOSE: To determine whether acute experimental glaucoma in rats obstructs retrograde transport of brain-derived neurotrophic factor (BDNF) to retinal ganglion cells (RGCs). METHODS: Forty rats had unilateral injection of either (125)I-BDNF (20 animals) or a mixture of (125)I-BDNF and 100-fold excess nonradiolabeled BDNF (20 animals). In each group of 20 animals, eyes contralateral to injection had either normal intraocular pressure (IOP; 10 animals) or IOP elevated to 25 mm Hg below the systolic blood pressure of the eye (10 animals). In each group of 20 rats, ipsilateral eyes had IOP set at systolic blood pressure (4 eyes), had optic nerve transection (10 eyes), or had normal IOP (6 eyes). Six hours after injection, animals were killed and tissues were fixed, embedded, and sectioned for autoradiography. Grain counts were performed over retina and optic nerve using automated image analysis. RESULTS: IOP elevation to 25 mm Hg below systolic blood pressure (perfusion pressure [PP] 25) decreased median retinal nerve fiber layer (NFL) grains by 38% compared with controls (P: < 0.001). Competition by cold BDNF reduced NFL grains by 28% (P: = 0.013). Considering only the radioactivity representing specific retrograde transport of BDNF, IOP elevation to PP25 reduced transport by 74%, whereas elevation to PP0 (equaling systolic blood pressure) reduced specific transport by 83%. CONCLUSIONS: BDNF is transported retrogradely from the superior colliculus in adult rats, and this transport is substantially inhibited by acute IOP elevation. Deprivation of BDNF among RGCs may contribute to neuron loss in glaucoma.

Acute Disease↗
PubMed1977

Retrograde axonal transport of horseradish peroxidase. Uptake at mouse neuromuscular junctions following systemic injection.

Eye muscles were examined histochemically for the presence of horseradish peroxidase (HRP) activity after intravenous injections of large doses of this tracer protein. HRP had penetrated through the blood vessels and diffused into the areas of motor end plates, where it outlined axon terminals at the synaptic clefts. HRP was incorporated into pinocytotic vesicles in the axons from where an intraaxonal transport in the retrograde direction to the nerve cell bodies in the brainstem followed. Accumulation of HRP in perikarya of motor neurons can therefore be the result of a physiological process of pinocytosis at the axon terminals. In this way exogenous macromolecules in the blood can by-pass the blood-brain barrier and reach the lower motor neurons in the CNS.

Animals↗
PubMed1979

The use of neurotoxins to characterize the rates and subcellular distributions of axonally transported dopamine-beta-hydroxylase, tyrosine hydroxylase and norepinephrine in the rat brain.

The effect of 6-hydroxydopamine (6-OHDA), colchicine and cytochalasin B on the transport and subcellular distribution of proteins, tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (DBH) and norepinephrine (NE) were studied in the noradrenergic neurons of the rat locus coeruleus (LC). Four waves of transported 3H-labeled proteins and glycoproteins, defined by previous studies, as well as hypothalamic levels of TH, DBH and NE, were examined after injection of each neurotoxin into the ascending dorsal noradrenergic bundle. Blockade of subcellular components of TH, DBH and NE was compared to their endogenous hypothalamic distributions. 6-Hydroxydopamine variably blocked transport of all 4 waves of 3H protein and bilateral injections decreased hypothalamic levels of TH, DBH and NE by 58.2, 56.9 and 52.2% of controls, respectively. Cytochalasin B blocked transport of protein waves I (72--192 mn/day) and III (13--20 mm/day) and decreased hypothalamic levels of TH to 60.1% of control after bilateral injections. Colchicine blocked transport of waves I, II (24--48 mm/day) and V (1.4--2.9 mm/day) and blocked [3H]NE transport, while decreasing hypothalamic levels of DBH and NE to 56.6 and 69.3% of control after bilateral injections. Colchicine and 6-OHDA, but not cytochalasin B, caused a backup of DBH immunofluorescence proximal to the injection site. DBH and NE appeared to be transported primarily in particulate form, while TH transport was predominantly soluble in distribution. None of the toxins differentially affected the transport of one particular subcellular component of TH, DBH or NE. Based on the differential blocking effects of these toxins, DBH and NE appeared to be associated with wave II, and TH with wave III, travelling at 24--48 mm/day and 13--20 mm/day respectively.

Animals↗
PubMed1977

Retrograde axonal transport of 125I-tetanus toxin as a tool for tracing fiber connections in the central nervous system; connections of the rostral part of the rat neostriatum.

After previous studies had shown that 125I-tetanus toxin is taken up with high efficiency by all (adrenergic, sensory and motor)peripheral nerve terminals and that it is transported retrogradely by intraaxonal transport to the corresponding cell bodies, the present experiments were designed to investigate whether 125I-tetanus toxin could be used as a tool for retrograde tracing of fiber connections in the central nervous system and how the results obtained compared with other available retrograde tracing methods. Three to 12 h after injection of 125I-tetanus toxin into the rostral part of the nucleus caudatus of the rat, heavily labeled nerve cells were found in the substantia nigra zona compacta, in Forel field H2 and parts of the zona incerta, and in specific thalamic intralaminar nuclei (nucleus medialis pars lateralis and nucleus parafascicularis). Moderately labeled neurons were observed in the nucleus ventralis thalami and its dorsomedial part, in the nucleus raphe dorsalis and in the frontal, cingular and occipital cortex. Besides the labeling by retrograde transport, orthograde transport of radioactivity occurred in a striatonigral system. The high sensitivity and reliability of this method, even after injection of very small amounts of protein in a very small volume, represent important advantages over most of the commonly used tracing methods.

Animals↗
PubMed1982

Retrograde axonal transport of a wheat germ agglutinin-horseradish peroxidase conjugate in Aplysia californica.

To begin examining retrograde transport in a single invertebrate neuron we have used wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP), 18 h after the conjugate was injected extracellularly into the neuropil of the buccal ganglion of Aplysia, HRP reaction product could be detected cytochemically in putative lysosomes, cisternae and vesicles near Golgi in the giant metacerebral neuron (GCN) of the cerebral ganglion. Appearance of reaction product in the cell body was blocked by ligating GCN's axon and was inhibited by colchicine.

Animals↗
PubMed2004

Basic fibroblast growth factor enhances transduction, distribution, and axonal transport of adeno-associated virus type 2 vector in rat brain.

The ubiquitous expression of cell surface heparan sulfate proteoglycan, a binding receptor for adeno-associated virus type 2 (AAV-2), may account for the broad host range of this vector. Because the fibroblast growth factor receptor type 1 has been postulated to be a coreceptor for successful AAV-2 entry into host cells, we designed a strategy to investigate whether coadministration of this virus with basic fibroblast growth factor (bFGF) can enhance AAV-2-mediated gene delivery. We injected AAV-2-thymidine kinase (AAV-2-TK) vector into rat striata and checked whether coinjection with bFGF enhanced transduction and/or enlarged the area of transgene expression. Immunostaining confirmed the tropism of AAV-2-TK for neurons. The previous injection (7 days before vector delivery) of bFGF had no major impact on vector distribution area. However, when the vector was coinjected with bFGF, the right striatum showed an average viral transduction volume of 5 mm(3), which was more than 4-fold larger when compared with the left side (AAV-2-TK plus phosphate-buffered saline). This result clearly indicates that simultaneous injection of bFGF with AAV-2-TK can greatly enhance the volume of transduced tissue, probably by way of a competitive block of AAV-2-binding sites within the striatum. Robust TK immunoreactivity was also observed in the globus pallidus, which receives anterograde projections from the striatum. We propose that postsynaptic transport of recombinant particles was likely responsible for the distribution of TK in the globus pallidus on both bFGF-treated and untreated sides. In summary, we found that bFGF acts as an adjuvant for distribution of AAV-2 in rat brain.

Animals↗
PubMed1978

Motor innervation of the urinary tract studied by retrograde axonal transport of protein.

A new method for tracing the nervous control of the bladder is described. A protein substance, horseradish peroxidase, has been shown to be absorbed and transported by nerve fibers. The substance was injected into the bladder neck region of a series of dogs. After uptake by motor neurons the horseradish was carried to the spinal cord segment controlling micturition. Implications regarding the neurophysiology of the urinary tract are discussed.

Animals↗
PubMed1985

Axonally transported Shigella cytotoxin is neuronotoxic.

Shigella dysenteriae strains produce an exotoxin (SdT) which inhibits protein synthesis in susceptible cells and is neurotoxic in some species. Intraneural microinjection of highly purified SdT into the cervical vagus nerves of rats, mice, guinea pigs and rabbits produced cytopathic changes within 24 hours in vagal sensory but not motor neurons. These changes consisted of an initial loss of Nissl substance followed by progressive cell degeneration and resulted in permanent neuronal loss. Indirect immunoperoxidase staining demonstrated SdT in nodose ganglion sensory neurons but not in vagal motor neurons of the brainstem. In rats, fatal enterotoxicity was common after intraneural injection of SdT doses that were reliably neuronotoxic; in rabbits and mice, a fatal ascending paralysis occurred at similar doses. Cytopathic changes were noted rarely in nodose sensory neurons of the uninjected side in mice suggesting systemic distribution and neuronal uptake of toxin. Injection of SdT into the tongue muscles of rats and mice failed to affect hypoglossal motor neurons within 50 hours. We conclude SdT is taken up and retrogradely transported by vagal sensory neurons with a resultant destruction of these neurons. The relationship of these findings to the reported neurotoxicity of SdT is unclear. However, SdT may prove useful in making selective lesions or as a model for some forms of neuronal degeneration.

Animals↗
PubMed1986

[Changes in axonal transport induced by ischemia].

Effect of ischemia, resulted from ligation of the abdominal part of the aorta, on the rate of anterograde and retrograde transport in the nervous pathways of the posterior roots has been studied in the canine spinal nerves. The anterograde transport rate is studied after injection of labelled 14C-leucine into spinal ganglia. An increased rate from 365 mm/day to 487 mm/day is revealed. The retrograde transport rate, that is estimated by means of horseradish peroxidase injected into the spinal cord, increases after the ischemia from 141 mm/day to 200 mm/day. A suggestion is made that the increase in the rate is caused by certain changes in ionic balance and osmosis produced by ischemia.

Adenosine Triphosphate↗
PubMed2005

Role of cytoplasmic dynein in the axonal transport of microtubules and neurofilaments.

Recent studies have shown that the transport of microtubules (MTs) and neurofilaments (NFs) within the axon is rapid, infrequent, asynchronous, and bidirectional. Here, we used RNA interference to investigate the role of cytoplasmic dynein in powering these transport events. To reveal transport of MTs and NFs, we expressed EGFP-tagged tubulin or NF proteins in cultured rat sympathetic neurons and performed live-cell imaging of the fluorescent cytoskeletal elements in photobleached regions of the axon. The occurrence of anterograde MT and retrograde NF movements was significantly diminished in neurons that had been depleted of dynein heavy chain, whereas the occurrence of retrograde MT and anterograde NF movements was unaffected. These results support a cargo model for NF transport and a sliding filament model for MT transport.

Actin Cytoskeleton↗