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PubMedDate not supplied

Nerve fiber regeneration following axotomy in the diabetic biobreeding Worcester rat: the effect of ARI treatment.

Diabetic neuropathy is characterized by progressive nerve fiber degeneration resulting in nerve fiber loss. In order to examine what role impaired nerve fiber regeneration may play in the progressive net nerve fiber loss, spontaneously diabetic biobreeding Worcester (BB/W) rats were subjected to sciatic nerve axotomy at 6 weeks of diabetes. Myelinated nerve fiber regeneration was examined morphologically and morphometrically at various time points following axotomy. The data were compared with those of axotomized control rats and diabetic rats treated with an aldose reductase inhibitor (ARI) from 1 week after onset of diabetes. Diabetic rats showed a significant attenuation of nerve fiber regeneration during the first 6 weeks following axotomy, which was normalized at 4 months postaxotomy. ARI treatment resulted in an initial burst of supranormal regeneration, which was normalized at 4 months postaxotomy. Impaired nerve fiber regeneration in diabetic rats was associated with a marked delay in preceding Wallerian degeneration and decreased phagocytic activity by macrophages, changes not demonstrated in ARI-treated diabetic rats. We propose that the impaired nerve fiber regeneration in the diabetic BB/W rat may, in part, be the result of impaired recruitment and/or function of macrophages necessary for the initiation of normal nerve fiber regeneration. The corrective effects of ARI treatment on the regenerative ability of diabetic peripheral nerve suggest that an activated polyol pathway may impact on both intrinsic and extrinsic mechanisms governing nerve fiber regeneration.

Aldehyde Reductase↗
PubMed1997

Effect of proximal axotomy on GAP-43 expression in cortical neurons in the mouse.

As an approach to understanding why central neurons fail to regenerate, we have studied the response to proximal axotomy of transcallosal neurons of the cerebral cortex of the mouse. Anatomical studies have indicated only very slight regenerative responses by this population of cortical neurons. To further examine the regenerative response of these cells, we have looked by in situ hybridization at the expression of GAP-43 mRNA following axotomy caused by a stab wound delivered within about 200 microm to 1.25 mm of the cell body. Axotomized transcallosal neurons were compared with near-by unaxotomized transcallosal neurons, as well as with distant unaxotomized cortical neurons in the contralateral hemisphere. All three populations of neurons had been pre-labeled with Fluoro-Gold to allow identification. No up-regulation of GAP-43 mRNA above background levels was detected for axotomized cortical neurons at 1, 3 or 7 days after injury. In contrast, increases in mean silver grain density of up to 8-fold were measured in axotomized spinal cord motor neurons used as positive controls. Thus, as a population, the transcallosal cortical pyramidal neurons did not show a significant regenerative response, as monitored by GAP-43 upregulation, even with very close axotomy. These results identify this population of neurons as among the least regenerative studied, and suggest that, on a molecular level, inherent neuronal properties play a role in the limited regenerative response to brain injury.

Animals↗
PubMed1996

aFGF, bFGF and NGF differentially regulate neuropeptide expression in dorsal root ganglia after axotomy and induce autotomy.

Using immunohistochemistry and in situ hybridization the in vivo effects of acidic and basic fibroblast growth factor (aFGF, bFGF), and of nerve growth factor (NGF) on the expression of galanin, neuropeptide Y (NPY) and substance P in axotomized dorsal root ganglia (DRGs) were examined. Self-mutilation (autotomy), a supposed pain-related behavior, was investigated after growth factor treatment. One microgram of aFGF, bFGF or NGF was applied directly to the transected sciatic nerve via a capsule. In normal rats 3.2%, 0% and 17.5% of the neuron profiles in the DRGs contained galanin-, NPY- and substance P-like immunoreactivity (LI), respectively. Sciatic nerve transection induced a distinct increase in galanin- and NPY-LIs, but a downregulation of substance P-LI. Thus three days after axotomy 23.5%, 26.9% and 9.8% of the DRG neuron profiles showed immunoreactivity for galanin-, NPY- and substance P-LI, respectively. In vivo administration of aFGF counteracted the axotomy-induced increase in galanin and NPY, whereas bFGF only suppressed NPY upregulation. NGF reversed in the injury-induced decrease in substance P-LI, but had no significant effect on galanin- and NPY-LIs. These results were confirmed by monitoring the mRNA levels for these neuropeptides. Moreover, aFGF was found to induce autotomy in 60% of the rats 3 days after axotomy. NGF produced autotomy in about 30% of the rats. Taken together, the present results suggest (1) that aFGF, bFGF and NGF differentially regulate neuropeptide expression in vivo; (2) that FGFs can inhibit neuropeptide upregulation of some peptides after nerve injury; and (3) that aFGF and NGF may induce pain-related behavior.

Animals↗
PubMed1997

YVAD protect post-natal retinal ganglion cells against axotomy-induced but not free radical-induced axonal degeneration in vitro.

In the developing central nervous system (CNS), the differentiation of neurons is accompanied by a large amount of cell loss in the form of programmed cell death (apoptosis). On the other hand, injury in the adult CNS often results in permanent neuronal degeneration leading to the failure of axonal regeneration. This could be related to an axotomy-induced activation of an apoptotic program. The interleukin-1beta-converting enzyme family of proteases has been implicated in playing a fundamental role in apoptotic processes in both invertebrates and vertebrates. In order to determine what role, if any, inhibitors of the interleukin-1beta-converting enzyme family might play in axonal regeneration after axotomy we employed an in vitro system using retinal explants from post-natal rats at the age between 9 and 12 days [R. Lucius, P. Young, S. Tidow and J. Sievers, Growth stimulation and chemotropic attraction of retinal ganglion cell axons in vitro by co-cultured optic nerves, astrocytes and astrocyte conditioned medium, Int. J. Dev. Neurosci., Vol. 14 (1996) 387-398]. The retinal ganglion cells in this model are comparable to adult animals in their regenerative response (D. Alcutt, M. Berry and J. Sievers, A qualitative comparison of the reaction of retinal ganglion cells to optic nerve crush in neonatal and adult mice, Dev. Brain Res., Vol. 16 (1984a) 231-240; D. Allcutt, M. Berry and J. Sievers, A quantitative comparison of the reaction of retinal ganglion cells to optic nerve crush in neonatal and adult mice, Dev. Brain Res., Vol. 16 (1984b) 219-230]. The addition of the synthetic peptide inhibitor YVAD (Ac-Tyr-Val-Ala-Asp-aldehyde), which reversible inhibits interleukin-1beta-converting enzyme and subsequent apoptosis, enhances the number and length of regenerating neurites of retinal ganglion cells. However, this manipulation was not able to overcome free radical-induced axonal degeneration/neuronal apoptosis, suggesting at least two different death pathways leading to neuronal degeneration/cell death. These results provide the first evidence that inhibitors of key enzymes of the apoptotic program could play a beneficial role to overcome neurite degeneration after axotomy in the adult mammalian CNS.

Animals↗
PubMed1993

Effects of axotomy on protein synthesis in the rat hypoglossal nucleus: examination of the influence of local recycling of leucine derived from protein degradation into the precursor pool.

The quantitative autoradiographic L-[1-14C] leucine method for the determination of regional rates of cerebral protein synthesis (lCPSleu) requires knowledge of the degree of recycling of leucine derived from protein degradation into the precursor pool for protein synthesis, which can be evaluated by measuring lambda i, the steady-state ratio of the leucine-specific activity in the precursor amino acid pool (tRNA-bound leucine) to that of the arterial plasma. To define the changes in lCPSleu during regeneration of the hypoglossal nerve, we examined the effects of axotomy on the value of lambda i. Because the concentration of tRNA-bound leucine in the hypoglossal nucleus is too low to measure, we measured the equivalent ratio for the total acid-soluble pool (psi i) and applied the linear relationship between lambda and psi found in the whole brain to calculate a value of lambda i in the ipsilateral and contralateral hypoglossal nuclei of 22 adult female rats 2, 18, 35, and 60 days after unilateral hypoglossal axotomy. Statistically significant but quantitatively inconsequential effects of axotomy on values of psi i and lambda i were found. Therefore, the mean value for lambda i (0.64) of the left and right hypoglossal nuclei in all 22 axotomized rats was used to calculate lCPSleu. In a separate group of 15 unilaterally axotomized rats, lCPSleu was determined by the autoradiographic technique; lCPSleu was increased on the axotomized side by 23% on day 2, 30% on day 18, and 13% on day 35. By postaxotomy day 60, lCPSleu had returned to normal.

Animals↗
PubMed1996

Induction of urokinase-type plasminogen activator in rat facial nucleus by axotomy of the facial nerve.

The response of plasminogen activator activity in the CNS to peripheral nerve axotomy was examined in vivo. After transection of the rat facial nerve, a transient increase in plasminogen activator activity was observed in the facial nucleus on the operated side with maximal activity 3-5 days after lesion. This activity was inhibited by the urokinase-specific inhibitor amiloride but not by antibodies against tissue plasminogen activator. The molecular mass of the induced form of plasminogen activator was estimated to be approximately 48 kDa. An in vitro assay of plasminogen hydrolysis also demonstrated an increase in amiloride-sensitive plasminogen activator activity in facial nerve extracts following facial nerve axotomy. These data indicate that the plasminogen activator activity induced in the facial nucleus following axotomy of facial motoneurons is of the urokinase type. It is suggested that the urokinase-type plasminogen activator might play a role in the events accompanying injury and regeneration in the facial nucleus following motoneuron lesion.

Animals↗
PubMed1996

Involvement of leukemia inhibitory factor in the increases in galanin and vasoactive intestinal peptide mRNA and the decreases in neuropeptide Y and tyrosine hydroxylase mRNA in sympathetic neurons after axotomy.

In response to axonal injury, noradrenergic sympathetic neurons of the adult superior cervical ganglion (SCG) alter their neurotransmitter phenotype. These alterations include increases in the levels of the neuropeptides, galanin, vasoactive intestinal peptide (VIP), and substance P (SP) and a decrease in the catecholamine biosynthetic enzyme tyrosine hydroxylase (TH). Previous studies have indicated that after axotomy in vivo, leukemia inhibitory factor (LIF) plays an important role in increasing the contents of galanin and VIP in the SCG. In the present study, by examining the time courses of the changes in LIF and neuropeptide mRNA and by using LIF null mutant mice, we have determined that LIF alters neuropeptide content in part by increasing levels of peptide mRNA. In addition, LIF also makes a small contribution to the axotomy-induced down-regulation of mRNA encoding TH and neuropeptide Y, both of which are normally expressed at high levels in the SCG. Finally, by using a LIF-blocking antiserum, this cytokine was found to regulate SP expression in an in vitro axonal injury model. Thus, after axotomy, a single factor, LIF, participates in the down-regulation of peptides/proteins involved in normal neurotransmission and the up-regulation of a group of neuropeptides normally not present in the SCG that may be involved in regeneration.

Animals↗
PubMed1996

Down-regulation of transcripts for Na channel alpha-SNS in spinal sensory neurons following axotomy.

Spinal sensory (dorsal root ganglion; DRG) neurons display slowly inactivating, tetrodotoxin-resistant (TTX-R), and rapidly inactivating, TTX-sensitive (TTX-S) Na currents. Attenuation of the TTX-R Na current and enhancement of TTX-S Na current have been demonstrated in cutaneous afferent DRG neurons in the adult rat after axotomy and may underlie abnormal bursting. We show here that steady-state levels of transcripts encoding the alpha-SNS subunit, which is associated with a slowly inactivating, TTX-R current when expressed in oocytes, are reduced significantly 5 days following axotomy of DRG neurons, and continue to be expressed at reduced levels, even after 210 days. Steady-state levels of alpha-III transcripts, which are present at low levels in control DRG neurons, show a pattern of transiently increased expression. In situ hybridization using alpha-SNS- and alpha-III-specific riboprobes showed a decreased signal for alpha-SNS, and an increased signal for alpha-III, in both large and small DRG neurons following axotomy. Reduced levels of alpha-SNS may explain the selective loss of slowly inactivating, TTX-R current. The abnormal electrophysiological properties of DRG neurons following axonal injury thus appear to reflect a switch in Na channel gene expression.

Animals↗
PubMed1987

Effects of preganglionic denervation and postganglionic axotomy on acetylcholine receptors in the chick ciliary ganglion.

The regulation of nicotinic acetylcholine receptors (AChRs) in chick ciliary ganglia was examined by using a radiolabeled anti-AChR mAb to quantitate the amount of receptor in ganglion detergent extracts after preganglionic denervation or postganglionic axotomy. Surgical transection of the preganglionic input to the ciliary ganglion in newly hatched chicks caused a threefold reduction in the total number of AChRs within 10 d compared with that present in unoperated contralateral control ganglia. Surgical transection of both the choroid and ciliary nerves emerging from the ciliary ganglion in newly hatched chicks to establish postganglionic axotomy led to a nearly 10-fold reduction in AChRs within 5 d compared with unoperated contralateral ganglia. The declines were specific since they could not be accounted for by changes in ganglionic protein or by decreases in neuronal survival or size. Light microscopy revealed no gross morphological differences between neurons in operated and control ganglia. A second membrane component of cholinergic relevance on chick ciliary ganglion neurons is the alpha-bungarotoxin (alpha-Bgt)-binding component. The alpha-Bgt-binding component also declined in number after either postganglionic axotomy or preganglionic denervation, but appeared to do so with a more rapid time course than did ganglionic AChRs. The results imply that cell-cell interactions in vivo specifically regulate both the number of AChRs and the number of alpha-Bgt-binding components in the ganglion. Regulation of these neuronal cholinergic membrane components clearly differs from that previously described for muscle AChRs.

Animals↗
PubMed1991

Regulation of aberrant neurofilament phosphorylation in neuronal perikarya. II. Correlation with continued axonal elongation following axotomy.

Neurofilaments (NF) are normally poorly phosphorylated in neuronal perikarya and highly phosphorylated in axons. Aberrant NF phosphorylation in the neuronal perikaryon has been demonstrated in a number of human and experimental disorders. In this study, we have asked whether expression of these phosphorylated NF (pNF) epitopes is dependent upon continued axonal regeneration following nerve transection (axotomy). This hypothesis was tested using the neurotoxic chemical acrylamide (AC) which is known to inhibit axonal regeneration following systemic administration. First, we examined whether AC acts at the level of the neuronal perikaryon to inhibit axonal elongation. Systemic, high dose intraperitoneal (IP) AC administration totalling 150 mg/kg (75 mg/kg x 2) did not impair the axotomy-induced reordering of slow axonal transport in the neuronal perikaryon. Next, we studied the ability of AC to directly prevent nerve outgrowth at the growing tips of axons. Subperineurial injection of AC (0.1 M), which in preliminary studies was found not to produce nerve fiber damage, markedly reduced the extent of nerve outgrowth when injected proximal to a nerve crush; this was shown by a reduction in the extent of radiolabeling and number of axonal sprouts in the distal stump seven days following nerve crush. Using this protocol, a 67% decrease in the number of neuronal perikarya in the L4 and L5 dorsal root ganglia demonstrating immunoreactivity to antibody 07-05 (directed against pNF epitopes) was observed in AC-injected compared to contralateral saline-injected crushed nerves. Taken together, the results indicate that inhibition of axonal regeneration in the distal stump by AC reduces aberrant NF phosphorylation in the neuronal perikaryon following axotomy.

Acrylamide↗
PubMed2005

Axotomy of sympathetic neurons activates the metalloproteinase-2 enzymatic pathway.

We have previously shown that intraganglionic synapse disassembly consequent on superior cervical ganglion (SCG) neuron axotomy was preceded by the loss of the dystroglycan beta subunit (beta-DG) localized at the postsynaptic specializations. Because DG, a transmembrane molecular complex bridging the extracellular matrix to the cortical cytoskeleton, could be a physiological target of metalloproteinases (MMPs) 2 and 9, we investigated their possible involvement in the injury-induced intraganglionic synapse disassembly. In rat SCG, only MMP-2 was present and localized in both neurons and nonneuronal cells. After ganglion neuron axotomy, both MMP-2 activity and protein level increased, whereas the level of its mRNA was unchanged, suggesting prominent MMP-2 posttranslational regulation. mRNA and protein levels of the enzymes involved in the MMP-2 activation pathway, the membrane-type 1-MMP (MT1-MMP), and the tissue inhibitor of metalloproteinase-2 (TIMP-2) also increased after injury with a time course that correlated with that of MMP-2 activation. In addition, postganglionic nerve crush induced an increase in the beta-DG 30-kDa fragment produced by the MMP-dependent degradation of DG. These data suggest that MMP-2 activated during SCG neuron reaction to axotomy may degrade postsynaptic DG, contributing to the disruption of the molecular bridge between pre- and postsynaptic elements and disassembly of the intraganglionic synapses.

Animals↗
PubMed1994

Motor neuron death induced by axotomy in neonatal mice occurs more slowly in a mutant strain in which Wallerian degeneration is very slow.

In contrast to motor neurons of adults, motor neurons of neonatal mice die if their axons are cut. We have examined the extent, the time course and the loss of susceptibility with age to such induced death in C57BL/Wlds mice. This is a strain which has a dominant autosomal mutation which dramatically slows the rate of degeneration of axons separated from their cell bodies. Following axotomy in neonatal animals the total number of motor neurons killed is no less in C57BL/Wlds mice than in two other strains (C57BL/6J/Ola and BALB/c/Ola). Indeed, the susceptibility to axotomy persists to a later age in C57BL/Wlds mice. However, the rate of cell death is significantly slower than in the two other strains; in C57BL/Wlds mice under a week old at the time of sciatic nerve section only approximately 16% of motor neurons have been lost 3 days after axotomy, whereas in the other mice approximately 45-84% of the final loss has by then occurred. This result extends previous work which showed that retrograde degeneration of retinal ganglion cells of adult mice was slower in C57BL/Wlds mice (V. H. Perry et al., Eur. J. Neurosci., 2, 408-413, 1991). It is therefore possible that Wallerian degeneration of axons shares features in common with retrograde nerve cell death and that the Wlds mutation may throw light on aspects of this complex process.

Aging↗
PubMed1995

NADPH diaphorase expression in the rat retina after axotomy--a supportive role for nitric oxide.

The large majority of mammalian retinal ganglion cells degenerate following section of their axons in the optic nerve. It has been suggested that some axotomized retina ganglion cells die because of toxic agents produced within their immediate environment. Our hypothesis was that nitric oxide might be one of the toxic factors implicated in the death of adult retinal ganglion cells post-axotomy. In the first instance, we determined whether there were any changes in the retinal expression of NADPH diaphorase both 3 and 14 days following intraorbital section of the optic nerve in adult rats. Secondly, if nitric oxide was indeed implicated in the death of ganglion cells, then trophic factors which rescue these neurons might do so by decreasing the expression of nitric oxide synthase. Recently, we found that a collicular proteoglycan purified from the major target of retinal ganglion cells, the superior colliculus, rescued a greater proportion of adult ganglion cells from axotomy-induced death than most other known trophic factors. We thus injected this proteoglycan intraocularly after section of the optic nerve and examined its effect on the expression of NADPH diaphorase in the retina. Thirdly, an inhibitor of nitric oxide synthetase was repeatedly injected into the eye following the section of the optic nerve in order to determine if such a treatment might improve the survival of retinal ganglion cells. The present results indicate that section of the optic nerve does not alter the overall levels of NADPH diaphorase within the adult rat retina. Intraocular injections of the collicular proteoglycan actually increased the number of neurons expressing NADPH diaphorase, particularly in the ganglion cell layer. Finally, inhibition of nitric oxide synthetase following axotomy resulted in increased loss of retinal ganglion cells over a 2 week period when compared with controls. Our findings indicate that, rather than being toxic, small amounts of nitric oxide may be important for the survival of a proportion of injured retina ganglion cells.

Animals↗
PubMed1995

Effect of collicular proteoglycan on the survival of adult rat retinal ganglion cells following axotomy.

Consistent with numerous previous studies, we have found that in adult rats 29% of cells retrogradely prelabelled by injections into retino-recipient nuclei are lost 1 week after intraorbital section of the optic nerve. This figure increases to 76% 2 weeks after axotomy. Intraocular injections of 150 ng of 480 kDa chondroitin sulphate proteoglycan purified from the superior colliculi of neonatal rats were performed every third day after axotomy. This procedure resulted in the loss of only 3 and 28% of the axotomized retinal ganglion cells 7 and 14 days respectively after optic nerve section. Intraocular injections of chondroitin sulphate type C, one of the sugar types present on the collicular proteoglycan, also resulted in a significant saving of axotomized ganglion cells (with the loss of only 48% 14 days after optic nerve lesion). These findings suggest that the collicular proteoglycan, and to a lesser extent its sugar moieties, substantially slows down the degeneration of adult retinal ganglion cells following axotomy.

Animals↗
PubMed1996

Regulation of VIP and other neuropeptides by c-Jun in sensory neurons: implications for the neuropeptide response to axotomy.

Peripheral axotomy of adult rat sensory neurons causes induction of the transcription factor c-Jun and increased expression of the neuropeptides vasoactive intestinal polypeptide (VIP), galanin and neuropeptide Y. To determine whether VIP induction is dependent on transcriptional regulation by c-Jun, we exploited the fact that c-Jun and VIP are also induced in cultured sensory neurons. We blocked c-Jun synthesis by microinjecting antisense oligonucleotides and found that VIP expression, determined by quantitative immunofluorescence, was specifically reduced. Blockade of c-June expression also resulted in reduced neuropeptide Y expression but left galanin, substance P and calcitonin gene-related peptide unaffected. Since in vitro electrophoretic mobility shift assays showed that a nominal cyclic AMP responsive element (CRE) associated with the rat VIP gene could bind c-Jun-containing transcription factor complexes, we next investigated whether VIP expression in sensory neurons might depend on transcription factor binding to the CRE. When a DNA plasmid containing multiple copies of the CRE was injected into newly cultured sensory neurons to sequester transcription factors binding the endogenous CRE, there was a selective reduction in VIP expression. VIP induction in sensory neurons therefore probably results from transcriptional activation by c-Jun acting in combination with other factor(s), possibly acting through the CRE. These results show that c-Jun can regulate transcription of other genes affected by axotomy and imply that it could be a key regulator of the neuronal axotomy response.

Animals↗
PubMed1990

Target regulation of axotomy-sensitive proteins.

Large changes in the production of certain proteins often follow axotomy. How the cell body is signaled to make these changes, or terminate them after regeneration is finished, is unclear. This issue was addressed by studying an axotomized giant identified neuron, the giant cerebral neuron of the sea slug Aplysia, both in vivo and in culture. One week after axon crush in vivo, there were increases of 1.5-18-fold in the 5-h incorporation of [35S]methionine into seven proteins identified by two-dimensional gel electrophoresis. There were decreases of five- to 28-fold in the labeling of four other proteins. An axotomized giant cerebral neuron grows vigorously when placed in culture and forms chemical synapses with appropriate target cells while continuing unabated growth. The labeling of two of the proteins that up-regulate after axotomy in vivo was suppressed by the presence of target cells in culture. For one of the proteins, this effect was also produced by membranes of target cells, but not by medium conditioned by exposure to target cells. These results are consistent with the idea that loss of membrane-membrane contact with target cells (or its restoration) is involved in the initiation (or termination) of the up-regulation of certain proteins after axotomy.

Animals↗
PubMed1990

Early changes in nuclear proteins following axotomy.

Changes in protein synthesis are thought to be important in the response of the neuron to axotomy. Certain axonally transported proteins whose synthesis increases probably play important roles in regeneration of the axon. Although little is known about the regulation of these changes, the cell often controls its production of proteins at the nuclear level, where transactivating proteins modulate the transcription of specific genes. Thus, changes in nuclear proteins might be expected to be among the early events following axotomy, but such changes have not yet been described. We have addressed this issue by dissecting out single nuclei from [35S]methionine-labeled giant R2 neurons of Aplysia and analyzing the proteins by two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis. This procedure was used to avoid contamination with nonneuronal and nonnuclear proteins. Our results demonstrate large increases in two nuclear proteins (56 kDa and 41 kDa) and decreases in two others (77 kDa and 46 kDa) 5 h after axotomy. These are the earliest postaxotomy changes in [35S]methionine-labeled proteins that have been reported.

Animals↗
PubMed1976

Physiological and morphological effects of post-ganglionic axotomy on presynaptic nerve terminals.

1. Electrophysiological and electron microscope studies were done on cells in the ciliary ganglion of chickens which had been axotomized on the day of hatching. 2. By the third day after post-ganglionic axotomy both electrical and chemical transmission through the ganglion were severely depressed; by the fifth day ganglionic transmission had disappeared. 3. Action potential initiation and conduction in axotomized cells and in their associated presynaptic nerve terminals were unimpaired 3-4 days after axotomy. 4. Depression of ganglionic transmission in 3-4 day axotomized preparations was due to a reduction in amplitude of both the excitatory post-synaptic potential (e.p.s.p.) and the electrical coupling potential in individual ganglion cells. 5. In addition to being reduced in amplitude, e.p.s.p.s in axotomized cells were more subject to fatigue during low frequency (1/sec) stimulation. 6. The reduction in e.p.s.p. amplitude was due to a reduction in both the mean quantal content of the e.p.s.p.s and the calculated depolarization produced by an individual quantum of transmitter. On the average the e.p.s.p. was reduced by a factor of about 4, the mean quantum content to about two thirds normal and the quantal size to about a third normal, compared with responses in unaxotomized cells of the same age. 7. Ultrastructural studies revealed a progressive maturation of pre-synaptic terminals in normal ganglia between 0 and 9 days after hatching. Over this period the content of synaptic vesicles and mitochondria in the terminals increased and the background matrix became more dense. 8. After axotomy these signs of maturation was abolished or reversed, particularly from the third day onward. In addition there was an increase in the number of cell sections in which no synaptic terminals were observed. 9. It was concluded that loss of synaptic transmission was due to at least three factors: a reduction in release of transmitter from presynaptic terminals, a reduction in quantal size, probably due to a loss of post-synaptic sensitivity, and a partial loss of presynaptic contact.

Action Potentials↗