Retardation of neuritic outgrowth and cytoskeletal changes accompany acetylcholinesterase inhibitor treatment in cultured rat dorsal root ganglion neurons

Dupree, Jeffrey L.; Bigbee, John W.

doi:10.1002/jnr.490390508

Cited by 74 publications

(50 citation statements)

References 37 publications

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“…Effects of the peripheral ligands of AChE on neuronal functions were examined, because the peripheral blockade of AChE inhibits neurite outgrowth (Layer et al, 1993;Dupree and Bigbee, 1994;Day and Greenfield, 2002) and alters the morphology of other cells (Calderon et al, 1998). On the 3rd or the 5th DIC, the neurons were treated with BW284c51, a membrane-impermeable, highly selective PAS inhibitor-ligand of AChE.…”

Section: Pas Blockade Impairs Glutamate Receptor Functionmentioning

confidence: 99%

Excessive Expression of Acetylcholinesterase Impairs Glutamatergic Synaptogenesis in Hippocampal Neurons

Dong¹,

Yun²,

Farchi³

et al. 2004

J. Neurosci.

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Acetylcholinesterase (AChE) exerts noncatalytic activities on neural cell differentiation, adhesion, and neuritogenesis independently of its catalytic function. The noncatalytic functions of AChE have been attributed to its peripheral anionic site (PAS)-mediated proteinprotein interactions. Structurally, AChE is highly homologous to the extracellular domain of neuroligin, a postsynaptic transmembrane molecule that interacts with presynaptic ␤-neurexins, thus facilitating synaptic formation and maturation. Potential effects of AChE expression on synaptic transmission, however, remain unknown. Using electrophysiology, immunocytochemistry, and molecular biological approaches, this study investigated the role of AChE in the regulation of synaptic formation and functions. We found that AChE was highly expressed in cultured embryonic hippocampal neurons at early culture days, particularly in dendritic compartments including the growth cone. Subsequently, the expression level of AChE declined, whereas synaptic activity and synaptic proteins progressively increased. Chronic blockade of the PAS of AChE with specific inhibitors selectively impaired glutamatergic functions and excitatory synaptic structures independently of cholinergic activation, while inducing AChE overexpression. Moreover, the PAS blockade-induced glutamatergic impairments were associated with a depressed expression of ␤-neurexins and an accumulation of other synaptic proteins, including neuroligins, and were mostly preventable by antisense suppression of AChE expression. Our findings demonstrate that interference with the nonenzymatic features of AChE alters AChE expression, which impairs excitatory synaptic structure and functions.

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Section: Pas Blockade Impairs Glutamate Receptor Functionmentioning

confidence: 99%

Excessive Expression of Acetylcholinesterase Impairs Glutamatergic Synaptogenesis in Hippocampal Neurons

Dong¹,

Yun²,

Farchi³

et al. 2004

J. Neurosci.

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“…AChE activity was detected histochemically as previously described (18,19,21), using acetylthiocholine as the substrate analog according to the modification of the method of El Badawi and Schenk (24). AChE activity was quantified either by colorimetric analysis based on the method of Ellman et al (25), using acetylthiocholine, or by radiometric assay, using tritiated acetylcholine, according to the method of Hall (26) as we have previously described (18,21).…”

Section: Ache Assaysmentioning

confidence: 99%

“…Address correspondence to J. W. Bigbee axonal outgrowth from these cells (1,8,9). In the peripheral nervous system (PNS), AChE is transiently expressed by developing dorsal root ganglion (DRG) neurons (10)(11)(12)(13)(14) and later in their axons and growth cones in the spinal cord (15,16 (18). BW284c51 is a bis-quaternary nitrogen compound that is a highly specific inhibitor for AChE.…”

mentioning

confidence: 99%

Morphogenic Role for Acetylcholinesterase in Axonal Outgrowth during Neural Development

Bigbee¹,

Sharma²,

Gupta³

et al. 1999

Environmental Health Perspectives

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Acetylcholinesterase (AChE) is the enzyme that hydrolyzes the neurotransmitter acetylcholine at cholinergic synapses and neuromuscular junctions. However, results from our laboratory and others indicate that AChE has an extrasynaptic, noncholinergic role during neural development. This article is a review of our findings demonstrating the morphogenic role of AChE, using a neuronal cell culture model. We also discuss how these data suggest that AChE has a cell adhesive function during neural development. These results could have additional significance as AChE is the target enzyme of agricultural organophosphate and carbamate pesticides as well as the commonly used household organophosphate chlorpyrifos (Dursban). Prenatal exposure to these agents could have adverse effects on neural development by interfering with the morphogenic function of AChE. -Environ Health Perspect 107(Suppl 1): 81-87 (1999). http.//ehpnetl.niehs.nih.gov/docs/1999/Suppl-1/81-B7bigbee/abstract.html

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“…This esterase activity is the target of widely used pesticides and pharmaceuticals (Mileson et al, 1998;Pope et al, 2005), yet the broad expression of AChE outside of the nervous system (Anderson et al, 2008;Bertrand et al, 2001;Bicker et al, 2004;Drews, 1975) and similarity to adhesion molecules (Botti et al, 1998;Darboux et al, 1996) suggest that it has additional functions. Indeed, in neuronal and non-neuronal cell lines, AChE promotes cell-substrate adhesion (Inkson et al, 2004;Johnson and Moore, 1999;Sharma et al, 2001;Syed et al, 2008), polarized cell migration (Anderson et al, 2008), cytoskeletal organization (Dupree and Bigbee, 1994;Keller et al, 2001) and cell differentiation (Grisaru et al, 1999;Xiang et al, 2008), independently of its esterase activity (Layer et al, 1993). However, the in vivo relevance of this putative multi-functionality is poorly substantiated, especially in non-neuronal contexts (Vogel-Hopker et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Acetylcholinesterase plays a non-neuronal, non-esterase role in organogenesis

2017

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Acetylcholinesterase (AChE) is crucial for degrading acetylcholine at cholinergic synapses. In vitro studies suggest that, in addition to its role in nervous system signaling, AChE can also modulate nonneuronal cell properties, although it remains controversial whether AChE functions in this capacity in vivo. Here, we show that AChE plays an essential non-classical role in vertebrate gut morphogenesis. Exposure of Xenopus embryos to AChE-inhibiting chemicals results in severe defects in intestinal development. Tissuetargeted loss-of-function assays (via microinjection of antisense morpholino or CRISPR-Cas9) confirm that AChE is specifically required in the gut endoderm tissue, a non-neuronal cell population, where it mediates adhesion to fibronectin and regulates cell rearrangement events that drive gut lengthening and digestive epithelial morphogenesis. Notably, the classical esterase activity of AChE is dispensable for this activity. As AChE is deeply conserved, widely expressed outside of the nervous system, and the target of many environmental chemicals, these results have wide-reaching implications for development and toxicology.

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Retardation of neuritic outgrowth and cytoskeletal changes accompany acetylcholinesterase inhibitor treatment in cultured rat dorsal root ganglion neurons

Cited by 74 publications

References 37 publications

Excessive Expression of Acetylcholinesterase Impairs Glutamatergic Synaptogenesis in Hippocampal Neurons

Excessive Expression of Acetylcholinesterase Impairs Glutamatergic Synaptogenesis in Hippocampal Neurons

Morphogenic Role for Acetylcholinesterase in Axonal Outgrowth during Neural Development

Acetylcholinesterase plays a non-neuronal, non-esterase role in organogenesis

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