Morphometric characterization of the neuromuscular junction of rodents intoxicated with 2,4-dithiobiuret: Evidence that nerve terminal recycling processes contribute to muscle weakness
Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI 48824, USA. Toxicology and Applied Pharmacology
(Impact Factor: 3.71).
05/2004; 196(2):266-86. DOI: 10.1016/j.taap.2004.01.004
2,4-Dithiobiuret (DTB) causes ascending motor weakness when given chronically to rodents. In muscles of animals with DTB-induced weakness, quantal release of acetylcholine (ACh) is impaired. We examined in detail the structural changes that occurred at neuromuscular junctions and their associated Schwann cells of extensor digitorum longus (EDL) muscles of male rats treated with DTB to the onset of muscle weakness, 5-8 days. Our objective was to assess the involvement of the Schwann cells and to determine the most likely primary targets of DTB. At the onset of muscle weakness, nerve terminals exhibited some enlarged regions, but did not sprout. Terminal Schwann cells became flatter and expanded to cover most of the endplate. The extent of invasion of the synaptic cleft by Schwann cell processes was not significantly different from controls; extension of Schwann cell sprouts away from the junction was not seen. Thus, the morphology of the Schwann cells, although clearly affected by DTB, does not suggest that they contribute directly to the physiological defects of DTB-treated terminals. Abnormal tubulovesicular structures or tangles of neurofilaments were clustered in the centers of about 25% of treated terminals. Fewer synaptic vesicles occupied the region opposite the postsynaptic folds. Vesicle volumes were variable and included some very large vesicles, corresponding with the variable MEPP amplitudes reported previously for terminals of DTB-treated rodents. The postsynaptic area stained by rhodamine-labeled alpha-bungarotoxin expanded with terminal swelling, apparently by unpleating of the postsynaptic folds. No loss of ACh receptors or spread of ACh receptors beyond terminal boundaries was detected. Morphometric data are consistent with the conclusion that DTB affects, either directly or indirectly, vesicular release of ACh and the subsequent vesicular recycling process.
Available from: Anne Giersch
- "The capacity of the STOP null axons to regenerate and project toward the OB glomeruli favors the second hypothesis. The tubulovesicular structures were similar to those observed in nerve terminals of the neuromuscular junction following intoxication with 2,4-dithiobiuret that are associated with a decrease of synaptic vesicles density, suggesting an impairment of vesicle release and recycling . At the presynaptic level, STOP protein is phosphorylated by calmodulin-dependant protein kinase II, an enzyme involved in synaptic plasticity. "
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ABSTRACT: STOP (Stable Tubulin-Only Polypeptide) null mice show behavioral deficits, impaired synaptic plasticity, decrease in synaptic vesicular pools and disturbances in dopaminergic transmission, and are considered a neurodevelopmental model of schizophrenia. Olfactory neurons highly express STOP protein and are continually generated throughout life. Experimentally-induced loss of olfactory neurons leads to epithelial regeneration within two months, providing a useful model to evaluate the role played by STOP protein in adult olfactory neurogenesis.
Immunocytochemistry and electron microscopy were used to study the structure of the glomerulus in the main olfactory bulb and neurogenesis in the neurosensorial epithelia. In STOP null mice, olfactory neurons showed presynaptic swellings with tubulovesicular profiles and autophagic-like structures. In olfactory and vomeronasal epithelia, there was an increase in neurons turnover, as shown by the increase in number of proliferating, apoptotic and immature cells with no changes in the number of mature neurons. Similar alterations in peripheral olfactory neurogenesis have been previously described in schizophrenia patients. In STOP null mice, regeneration of the olfactory epithelium did not modify these anomalies; moreover, regeneration resulted in abnormal organisation of olfactory terminals within the olfactory glomeruli in STOP null mice.
In conclusion, STOP protein seems to be involved in the establishment of synapses in the olfactory glomerulus. Our results indicate that the olfactory system of STOP null mice is a well-suited experimental model (1) for the study of the mechanism of action of STOP protein in synaptic function/plasticity and (2) for pathophysiological studies of the mechanisms of altered neuronal connections in schizophrenia.
PLoS ONE 09/2010; 5(9):e12753. DOI:10.1371/journal.pone.0012753 · 3.23 Impact Factor
Available from: toxsci.oxfordjournals.org
- "There is growing evidence that the function of chemical synapses in the peripheral nervous system (PNS) and central nervous system (CNS) can be disrupted by many structurally dissimilar electrophilic neurotoxicants, e.g., acrylamide, 2,4- dithiobiuret, methylmercury, acrolein, and diethyldithiocarbamate (Table 1; Atchison and Narahasi, 1982; Atchinson et al., 1982; Danscher et al., 1973; Goldstein and Lowndes, 1979, 1981; LoPachin et al., 2004; Xu et al., 2002). Results from corresponding research have suggested both pre-and postsynaptic sites (e.g., neurotransmitter postsynaptic receptors and presynaptic uptake, storage, and release) as possible targets for these chemicals (LoPachin et al., 2004, 2006a; Lovell et al., 2000; Nagendra et al., 1997; Rheuben et al., 2004; Vaccari et al., 1998). Whereas the molecular mechanisms of these synaptic toxicants are poorly understood, they share the ability to form adducts with or otherwise modify nucleophilic sulfhydryl groups (Barber and LoPachin, 2004; Clarkson, 1972; Kruzer, 1956; Witz, 1989). "
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ABSTRACT: Many structurally diverse chemicals (e.g., acrylamide, 2,4-dithiobiuret, methylmercury) are electrophiles and cause synaptic dysfunction by unknown mechanisms. The purpose of this Forum review is to discuss the possibility that highly nucleophilic cysteine thiolate groups within catalytic triads of synaptic proteins represent specific and necessary targets for electrophilic neurotoxicants. Most of these toxicants share the ability to adduct or otherwise modify nucleophilic sulfhydryl groups. It is also now recognized that synaptic activity is regulated by the redox state of certain cysteine sulfhydryl groups on proteins. Electrophilic neurotoxicants might, therefore, produce synaptic toxicity by modifying these thiols. Because most proteins contain cysteine residues, target specificity is an issue that significantly detracts from the mechanistic validity of this hypothesis. However, recent research indicates that these thiolates are receptors for the endogenous nitric oxide (NO) pathway and that subsequent reversible S-nitrosylation finely regulates a broad spectrum of synaptic activities. We hypothesize that electrophilic neurotoxicants selectively adduct/derivatize NO-receptor thiolates in catalytic triads and that the resulting loss of fine gain control impairs neurotransmission and produces neurotoxicity. This proposal has mechanistic implications for a large class of electrophilic chemicals used in the agricultural and industrial sectors. In addition, research based on this hypothesis could provide mechanistic insight into neurodegenerative conditions such as Parkinsonism and Alzheimer's disease that presumably involve endogenous production of neurotoxic electrophiles (e.g., acrolein, 4-hydroxy-2-nonenal). The proposed mechanism of electrophilic neurotoxicants represents a new and exciting experimental framework for mechanistic research in human neuropathological conditions associated with toxicant exposure or disease-based processes.
Toxicological Sciences 01/2007; 94(2):240-55. DOI:10.1093/toxsci/kfl066 · 3.85 Impact Factor
Biochemistry and Cell Biology 01/1961; 39(4):787-827. DOI:10.1139/o61-081 · 2.15 Impact Factor
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