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PubMed1988

Calcium dependent modulation of fast axonal transport.

The highly differentiated structure of the neuron poses special problems for the intracellular movement of molecules throughout the cell. Molecular transport distances from the synthesizing neuron cell body along the axon (which has no substantial synthetic capabilities) to the axon terminal are very great. The transported substances, transport support structures, translocator motors, and control elements are currently the focus of intense research. Interruption of this flow of molecules could have disastrous effects upon the cell and ultimately the organism resulting in neuropathological conditions. Calcium plays a critical role in modulating fast-axonal transport (FAT) speeds. Before discussing the effect of calcium on FAT, we summarize our broad perspective on the role of axonal transport in neurologic disease.

Amyotrophic Lateral Sclerosis↗
PubMed1982

Axonal transport interruption and anatomy at the lamina cribrosa.

Pressure-induced, focal axonal transport abnormalities were studied in 14 cat eyes by the examination of serial step-section tissue radioautogram. Although the patterns of the transport interruption at the lamina cribrosa varied from eye to eye, the temporal sectors of the nerve head were most often involved by this abnormality. The anatomy at the lamina cribrosa was studied in adjacent (6 micrometers) cross-sectional specimens. The thickness of the extra-bundle trabeculae and the nerve fiber bundle dimensions including the cross-sectional area and the number and the shape (the ratio of the major and the minor axis diameters) of the laminar pores were measured by computer-assisted perimeter analysis. There was no correlation between the location of the transport interruption and any of these anatomic measurements.

Animals↗
PubMed1993

GAP 43-like immunoreactivity in normal adult rat sciatic nerve, spinal cord, and motoneurons: axonal transport and effect of spinal cord transection.

Using immunofluorescence and cytofluorimetric scanning techniques in the rat, the fast anterograde and retrograde axonal transport of growth-associated protein-43-like immunoreactivity in normal sciatic nerves, and after spinal cord transection in the lower thoracic region, were investigated. Spinal roots and motor endplates in the peroneal muscles were also studied. For comparison, anti-synaptophysin (p38) was used. In intact adult animals, the amounts of immunoreactive growth-associated protein-43 increased linearly, both proximally and distally to the crush site, between 1 and 24 h after crushing the sciatic nerve. The accumulations were present in thick as well as in thin axons. Distal accumulations in the sciatic nerve were about 40-60% of the proximal amounts, indicating a recycling of organelles with growth-associated protein-43-like immunoreactivity. During the week after spinal cord transection, no clear changes were observed; the anterograde transport of growth-associated protein-43-like immunoreactivity showed a tendency to decrease at day 1 and then a tendency to increase, reaching 120% of control at seven days (not significant). Transported p38-like immunoreactivity showed similar but smaller changes. In the lumbar spinal cord gray matter many nerve terminals with growth-associated protein-43-like immunoreactivity were seen in intact animals. After spinal transection, these terminals gradually decreased, suggesting that they belonged to descending pathways. However, p38-positive terminals were not obviously decreased. After crushing ventral and dorsal roots, accumulations of pf growth-associated protein-43-like immunoreactivity were present in thick axons in the ventral roots and in thin to medium-sized axons in the dorsal roots. In peroneal muscles, growth-associated protein-43-like immunoreactivity was present in some (but not all) motor endplates in all groups. These results indicate that: (i) growth-associated protein-43 is normally present in nerve terminals of many descending projections of the spinal cord; (ii) growth-associated protein-43-like immunoreactivity is expressed and bidirectionally transported in neurons (motor as well as sensory) of normal sciatic nerves; (iii) growth-associated protein-43-like immunoreactivity is present in some adult motor endplates; and (iv) inhibited supraspinal input causes minor, if any, alterations--paralleled by p38--in axonal transport of growth-associated protein-43-like immunoreactivity.

Animals↗
PubMed1990

[The comparative characteristics of the age-related changes in the rate of fast axonal transport in the vagus and hypoglossal nerves and in the ventral spinal cord roots of rats].

The study was undertaken on the fast axonal transport (FAT) of 3H- or 14C-leucine labelled substances along the n. vagus, n. hypoglossus and ventral roots of the spinal cord in adult (8-10 months) and old (26-28 months) male rats after the label administration into nucleus ambiguus, nucleus hypoglossus, and the area of the ventral horn of the spinal cord, respectively. It has been found that in old rats compared to adult animals the rate of FAT along the n. vagus decreased from 552 +/- 12.7 mm to 252 +/- 13 mm per 24 hours; along the n. hypoglossus--from 492 +/- 38 mm to 216 mm per 24 hours; and along the ventral L5 and L6 roots--from 408 +/- 10.9 mm to 217 +/- 11.3 mm per 24 hours. It is suggested that age-related functional shifts in n. vagus influencing the heart are, to some degree, determined by the most significant disturbances of FAT substances in it.

Aging↗
PubMed1982

Divalent cations and fast axonal transport in chemically desheathed (Triton X-treated) frog sciatic nerve.

We have studied the ability of divalent cations to restore to normal axonal transport (AXT) which was inhibited by deprivation of Ca2+ and/or Mg2+ ions. The epi- and perineurium of the frog sciatic nerve were damaged by a 30-s wash in Triton X-100 containing frog Ringer's. This treatment did not affect either AXT or nerve levels of Ca2+ and Mg2+, but made the ions more easily extractable with a Ca2+- and Mg2+-free Ringer's solution (CMFR). Inhibition of AXT was achieved by incubating Triton X-100-treated nerves in CMFR + EGTA for 5 h, followed by an additional incubation for 12 h in CMFR or Ringer's devoid of only Ca2+ (CFR). These treatments reduced Ca2+ and Mg2+ contents by 77% and 38% respectively. Addition of Ca2+ (1.1 mM) during the 12-h period stimulated AXT, measured as accumulation of 3H-labelled components in front of a ligature, several fold. Mg2+ could not substitute for Ca2+ but potentiated the stimulating effect of Ca2+. Addition of other divalent cations did not affect AXT (Sr2+ and Ba2+) or potentiated the inhibition caused by Ca2+-deprived medium (Mn2+ and Co2+). ATP and creatine phosphate contents were similar in nerves incubated in Ca2+-deprived medium and in Ca2+-containing Ringer's. Thus, inhibition of AXT in the former situation was not due to a decreased availability of high energy phosphates. Two calcium antagonists, D-600 and nifedipin, which are potent smooth muscle relaxants, effectively blocked AXT. The present results suggest that Ca2+ is specifically required to maintain AXT and that an analogy exists between Ca2+ regulation during smooth muscle contraction and AXT.

Animals↗
PubMed1977

Identification of different size motoneurons labeled by the retrograde axonal transport of horseradish peroxidase.

Three main groups of motoneurons of different size have been labeled in adult cats by using the method for retrograde axonal transport following injection of horseradish peroxidase in the medial gastrocnemius and soleus muscles. In particular small, medium-size and large neurons which probably correspond respectively to gamma, small alpha and large alpha motoneurons innervating the calf muscles, have been identified and the corresponding area measured.

Animals↗
PubMed1981

Inhibition of rapid axonal transport in vitro by the ionophores X-537 A and A 23187.

The effects of the ionophores X-537 A and A 23187 on axonal transport (AXT)' high energy phosphates, levels of Ca2+ and ultrastructure were investigated in frog sciatic nerves in vitro. X-537 A at 0.09 muM blocked AXT of [3H]labelled proteins by 50% as judged by ligature experiments while the levels of ATP and CrP remained unchanged. Pulse-label experiments showed that the amount of transported material decreased whereas the rate of AXT was only slightly retarded. Elevated extracellular levels of Ca2+ (5mM) potentiated the inhibitory effect of the ionophore. In contrast, ruthenium red counteracted the ionophore induced inhibition of AXT. A 23187 at 10 muM but not at 2 muM inhibition AXT but also reduced the ATP and CrP levels. In pulse-label experiments A 23187 displayed similar but less pronounced effects than X-537 A. Both ionophores increased the total calcium content of the nerve and appeared to decrease the amount of axonal mictotubles (MT). As X-537 is a very potent inhibitor of AXT it may prove a valuable tool in exploring the relations between AXT, Ca2+ and MT.

Adenosine Triphosphate↗
PubMed1986

Quantitative comparison between tetanus toxin, some fragments and toxoid for binding and axonal transport in the rat.

The fragments BIIb and C of tetanus toxin, which contain its binding domain, were quantitatively compared with native toxin and a toxoid with respect to axonal transport from the gastrocnemius muscle to the spinal cord in rats. Against 125I-toxin, the dose-ascent curve of labelled toxoid was shifted by a factor of 3-5 to higher concentrations, whereas the ascent of the labelled binding fragments was at least 50-100 times less. The binding fragments also differed from tetanus toxin by their very low affinity to rat brain membranes buffered to pH 7.5 in saline, but were equivalent with the toxin in buffer of low molarity and low pH. We conclude that additional parts of the toxin molecule have to complement the binding domain for expression of the full binding and transport characteristics of the toxin.

Animals↗
PubMed1987

Fast axonally transported proteins in regenerating goldfish optic nerve: effect of abolishing electrophysiological activity with TTX.

Blocking neural activity with intraocular tetrodotoxin (TTX) hinders regeneration of goldfish optic axons, and prevents the refinement of the retinotopic map that is formed in the optic tectum. The latter effect is not observed with TTX treatment confined to the first two weeks of regeneration, but is produced when the TTX treatment is delayed until after this time. In the present study, 2-dimensional gel electrophoresis was used to analyse the effects of two different schedules of TTX treatment (0-9 days or 14-32 days) on incorporation of [3H]proline into individual proteins conveyed by fast axonal transport in the optic nerve. The labelling of many of these proteins was somewhat reduced by either schedule of TTX treatment, but a number of proteins showed a larger reduction as a result of the delayed treatment. These included some glycoproteins, as well as a protein of about 45 kDa and pI 4.5, which shows greatly increased synthesis during regeneration, and which is probably identical to the 'growth-associated protein' GAP-43. By contrast, cytoskeletal proteins (alpha- and beta-tubulin and actin) were unaffected by the delayed TTX treatment. It is possible that the differential effects of the early and delayed TTX treatments on various transported proteins may account for differences in the effect of these treatments on the retinotectal projection.

Animals↗
PubMed1981

Retrograde axonal transport. A possible role in the development of neuropathy.

The accumulation of 3H-fucose labelled glycoprotein and 35S-methionine labelled protein carried by the retrograde axonal transport in the sensory fibres of the sciatic nerve was examined on the day after injection of streptozotocin in rats. The accumulation of fucose-label was reduced (2.8 +/- 0.4 (SD) versus 2.1 +/- 0.5 (arbitrary units), 2p = 0.0044) indicating a decreased retrograde flux of glycoproteins. This early transport abnormality could have a key role in the development of peripheral neuropathy in diabetes.

Animals↗
PubMed1979

Nerve growth factor (NGF) in the rat CNS: absence of specific retrograde axonal transport and tyrosine hydroxylase induction in locus coeruleus and substantia nigra.

Selective, highly efficient uptake of [125I]NGF by nerve terminals followed by retrograde axonal transport, and specific induction of tyrosine hydroxylase by NGF are well known phenomena in peripheral adrenergic neurons of adult rats. In the present study these parameters were used in order to detect possible interactions of NGF with central catecholaminergic neurons. No selective retrograde transport of [125I]NGF could be detected by light microscopic autoradiography from the caudate nucleus to the dopaminergic neurons in the substantia nigra or from the hippocampus to the noradrenergic nerve cells of the locus coeruleus. Biochemically, no change in tyrosine hydroxylase activity could be observed for up to 3 days after injection of either NGF, anti-NGF antibodies, or control proteins close to the nerve cell bodies in the substantia nigra or the locus coeruleus. These data suggest a fundamental difference between central and peripheral adrenergic neurons with regard to their responsiveness of NGF.

Adrenergic Fibers↗
PubMed1980

An axonal transport study of the ascending projection of medial lemniscal neurons in the rat.

The pattern of projection of the rat medial lemniscus was studied by axonal transport labeling following injections of tritiated leucine, proline and/or adenosine, or of horseradish peroxidase for retrograde identification of the neurons of origin. The vast majority of neurons in the gracile, cuneate, and principal trigeminal nuclei contribute to an almost totally crossed projection primarily to the thalamic ventrobasal complex. Additional thalamic components were traced to specific sites within the "posterior group," including a medial component largely traversed by lemniscal axons and a caudolateral component lying between the principal nucleus of the medial geniculate and ventral nucleus of the lateral geniculate. We have designated this latter zone "intermediate geniculate," distinguishing a somatosensory portion of the geniculate group on the basis of its myelo- and cytoarchitecture, as well as its connections. Other projections replicated in several animals included the zona incerta and nearby sectors of the substantia nigra; three distinct mesencephalic arrangements within the deep layers of the superior colliculus, the external nucleus of the inferior colliculus, and the intercollicular nucleus; the anterior pretectal nucleus; dorsal sectors of the inferior olivary complex and the ipsilateral cerebellar cortex. The results are compared with findings in other species (with emphasis on the caudal thalamic region) in an attempt to resolve some of the apparent inconsistencies in nomenclature.

Afferent Pathways↗
PubMed1982

Effects of phenothiazines and dibenzazepines on axonal transport and microtubule assembly in vitro.

Various phenothiazines (thioridazine, trifluoperazine and chlorpromazine) and dibenzazepines (lofepramine, amitriptyline and desipramine) were studied for effects on fast axonal transport (AXT) in vitro in frog sciatic nerves. AXT, measured as the accumulation of (3H) leucine-labelled proteins in front of a ligature, was inhibited by more then 50% by all the drugs tested at 0.2 mM concentrations. Thioridazine and lofepramine were the most potent inhibitors. These effects were not due to decreased ganglionic incorporation. Some of the drugs also reduced the levels of high energy phosphates, adenosinetriphosphate (ATP) and creatinephosphate (CrP), but not to an extent which is likely to explain the arrested AXT. The polymerization of purified brain tubulin was inhibited by the phenothiazines but unaffected by the dibenzazepines at concentrations which inhibited AXT. Phenothiazines and dibenzazepines are chemically related and known to have a high affinity for calmodulin. The possibility that these drugs interefere with calmodulin regulated processes of importance for AXT will be discussed.

Adenosine Triphosphate↗
PubMed1978

Rapid orthograde and retrograde axonal transport of acetylcholinesterase as characterized by the stop-flow technique.

1. In rabbit peroneal nerves incubated in vitro at 37 degrees C, acetylcholinesterase (AChE) activity accumulated at both borders of a short region cooled to 5 degrees C. Accumulation was unaffected by concentrations of cycloheximide that inhibited 86% of local protein synthesis, as measured by the incorporation of [3H]leucine. It is probable that the local changes in enzyme activity during incubation reflected redistribution of the enzyme by axonal transport. 2. AChE activity accumulated almost three times faster at the proximal than at the distal border of cooled regions. This suggests that three times more enzyme is normally exported from nerve cell bodies than is returned to them, as though most of the transported AChE were degraded or secreted from distal parts of the neurones. The rates of accumulation of enzyme activity were consistent with average velocities of transport of 24 mm/day in the distal (orthograde) direction and 8.6 mm/day in the proximal (retrograde) direction. 3. When nerves that had been locally cooled for 3 hr were rewarmed to 37 degrees C, the accumulated AChE activity moved rapidly away from the cooled region. More than half of the activity appeared in a wave moving distally with a maximum velocity of 400 +/- 35 mm/day. A smaller wave moved proximally with a maximum velocity of 288 mm/day. 4. The observed behaviour of AChE is direct evidence that a small amount of this enzyme, probably less than 10% of the axonal content, is normally transported away from cell bodies as rapidly as any substance known. A still smaller amount of the enzyme is subject to an almost equally rapid retrograde transport. However, 85% of the AChE in peripheral nerve appears to be stationary, which probably explains why the average velocity of transport of this enzyme is so low.

Acetylcholinesterase↗
PubMed1994

Regenerating peripheral axons transport and release low-molecular-mass materials in vitro.

The release of radiolabeled material from regenerating frog sciatic nerves was studied using a multicompartment chamber, in which the ganglia and the outgrowth region, respectively, were separated from the rest of the nerve. The nerves were incubated with radioactive amino acids in the ganglionic compartment, and the material transported to and released at the outgrowth region was collected and analyzed. Approximately 10% of the transported radioactivity was released over a 24-h incubation period. Of the released materials, 84% had a molecular mass of < 1,000 daltons [the low-molecular-mass (LM) fraction] as determined by exclusion chromatography. The presence of LM material could not be explained by leakage, nor was it due to intracellular or extracellular degradation of radiolabeled, transported proteins. It was reduced by cold and was shown by the use of vinblastine to be dependent on axonal transport. According to TLC, both the original precursor and metabolites thereof could be detected among the released LM material. The present results demonstrate the existence of a transport system for LM material in peripheral axons. The preferential release of LM over high-molecular-mass material at the outgrowth region suggests that it could serve specific functions during regeneration.

Animals↗