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Ziram, a pesticide associated with increased risk for Parkinson's disease, differentially affects the presynaptic function of aminergic and glutamatergic nerve terminals at the Drosophila neuromuscular junction

Martin, Ciara A. and Myers, Katherine M. and Chen, Audrey and Martin, Nathan T. and Barajas, Angel and Schweizer, Felix E. and Krantz, David E. (2016) Ziram, a pesticide associated with increased risk for Parkinson's disease, differentially affects the presynaptic function of aminergic and glutamatergic nerve terminals at the Drosophila neuromuscular junction. Experimental Neurology, 275 (1). pp. 232-241. ISSN 0014-4886. PMCID PMC4688233. https://resolver.caltech.edu/CaltechAUTHORS:20151012-141107666

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Abstract

Multiple populations of aminergic neurons are affected in Parkinson's disease (PD), with serotonergic and noradrenergic loci responsible for some non-motor symptoms. Environmental toxins, such as the dithiocarbamate fungicide ziram, significantly increase the risk of developing PD and the attendant spectrum of both motor and non-motor symptoms. The mechanisms by which ziram and other environmental toxins increase the risk of PD, and the potential effects of these toxins on aminergic neurons, remain unclear. To determine the relative effects of ziram on the synaptic function of aminergic versus non-aminergic neurons, we used live-imaging at the Drosophila melanogaster larval neuromuscular junction (NMJ). In contrast to nearly all other studies of this model synapse, we imaged presynaptic function at both glutamatergic Type Ib and aminergic Type II boutons, the latter responsible for storage and release of octopamine, the invertebrate equivalent of noradrenalin. To quantify the kinetics of exo- and endo- cytosis, we employed an acid-sensitive form of GFP fused to the Drosophila vesicular monoamine transporter (DVMAT-pHluorin). Additional genetic probes were used to visualize intracellular calcium flux (GCaMP) and voltage changes (ArcLight). We find that at glutamatergic Type Ib terminals, exposure to ziram increases exocytosis and inhibits endocytosis. By contrast, at octopaminergic Type II terminals, ziram has no detectable effect on exocytosis and dramatically inhibits endocytosis. In contrast to other reports on the neuronal effects of ziram, these effects do not appear to result from perturbation of the UPS or calcium homeostasis. Unexpectedly, ziram also caused spontaneous and synchronized bursts of calcium influx (measured by GCaMP) and electrical activity (measured by ArcLight) at aminergic Type II, but not glutamatergic Type Ib, nerve terminals. These events are sensitive to both tetrodotoxin and cadmium chloride, and thus appear to represent spontaneous depolarizations followed by calcium influx into Type II terminals. We speculate that the differential effects of ziram on Type II versus Type Ib terminals may be relevant to the specific sensitivity of aminergic neurons in PD, and suggest that changes neuronal excitability could contribute to the increased risk for PD caused by exposure to ziram. We also suggest that the fly NMJ will be useful to explore the synaptic effects of other pesticides associated with an increased risk of PD.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1016/j.expneurol.2015.09.017DOIArticle
http://www.sciencedirect.com/science/article/pii/S0014488615300996PublisherArticle
ORCID:
AuthorORCID
Chen, Audrey0000-0003-2139-9535
Additional Information:© 2015 Elsevier B.V. Received 6 April 2015, Revised 4 September 2015, Accepted 26 September 2015, Available online 9 October 2015. This work was conducted with funding from the National Institute of Environmental Health and Safety (NIEHS), UCLA training grant in Molecular Toxicology, USHHS Ruth L. Kirschstein Institutional National Research Service Award T32 ES015457, (C.A.M. pre-doctoral), NIEHS R01-ES015747 and NIMH R01-MH076900 (D.E.K.), NINDS R21-NS075506 (F.E.S), funding from the Parkinson’s Disease Foundation (PDF-SFW-1336 to C.A.M.), from The Brain and Behavior Research Foundation and the Joanne and George Miller and Family Endowed Chair in Depression Research at the UCLA Brain Research Institute (D.E.K.), a pilot grant through the National Center for Advancing Translational Sciences UCLA CTSI Grant UL1TR000124 (F.E.S.) and an NIEHS program project grant ES016732 (M.F. Chesselet, PI).
Funders:
Funding AgencyGrant Number
UCLA training grantUNSPECIFIED
U.S. Dept. of Health & Human Services (USHHS)T32 ES015457
National Institute of Environmental Health and Safety (NIEHS)R01-ES015747
National Institute of Mental Health (NIMH)R01-MH076900
National Institute of Neurological Disorders and Stroke (NINDS)R21-NS075506
Parkinson’s Disease FoundationPDF-SFW-1336
Brain and Behavior Research FoundationUNSPECIFIED
UCLA Brain Research InstituteUNSPECIFIED
National Center for Advancing Translational SciencesUL1TR000124
National Institute of Environmental Health and Safety (NIEHS)ES016732
Issue or Number:1
PubMed Central ID:PMC4688233
Record Number:CaltechAUTHORS:20151012-141107666
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20151012-141107666
Official Citation:Ciara A. Martin, Katherine M. Myers, Audrey Chen, Nathan T. Martin, Angel Barajas, Felix E. Schweizer, David E. Krantz, Ziram, a pesticide associated with increased risk for Parkinson's disease, differentially affects the presynaptic function of aminergic and glutamatergic nerve terminals at the Drosophila neuromuscular junction, Experimental Neurology, Volume 275, Part 1, January 2016, Pages 232-241, ISSN 0014-4886, http://dx.doi.org/10.1016/j.expneurol.2015.09.017. (http://www.sciencedirect.com/science/article/pii/S0014488615300996)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:61006
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:15 Oct 2015 21:09
Last Modified:03 Oct 2019 09:03

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