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ToxSci Advance Access published online on October 7, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp244
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Reduction of glutamatergic neurotransmission by prolonged exposure to dieldrin involves NMDA receptor internalization and metabotropic glutamate receptor 5 down-regulation

Victor Briz*,{dagger}, Mireia Galofré*,{dagger} and Cristina Suñol*,{dagger}

* Department of Neurochemistry and Neuropharmacology. Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas, CSIC – IDIBAPS, E-08036 Barcelona, Spain {dagger} CIBER Epidemiología y Salud Pública (CIBERESP), Spain

Corresponding author: Dr. Cristina Suñol, Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomèdiques de Barcelona, CSIC-IDIBAPS. Rosselló 161. 08036 Barcelona, Spain. Tel: (+34) 93 363 83 18, Fax: (+34) 93 363 83 01, E-mail: csenqi{at}iibb.csic.es

Received August 4, 2009; revision received September 23, 2009; accepted September 23, 2009


  Abstract

Dieldrin was previously used as a pesticide. Although its use has been discontinued, humans are still exposed to it due to its high environmental persistence and because it accumulates in the adipose tissue of animals. Acute exposure to dieldrin provokes convulsions, due to its antagonism on the GABAA receptor. However little is known about the effects of low chronic exposure to this pollutant. In the present work we use primary cultures of cortical neurons to study the mechanisms involved in the toxic action of dieldrin. We found that 2 and 6 days in vitro (DIV) exposure to a subcytotoxic concentration (60nM) of dieldrin reduced the increase in intracellular calcium concentration ([Ca2+]i) and the excitotoxicity caused by glutamate. Exposure to dieldrin for 6 DIV induced NMDA receptor (NMDAR) internalization and reduced metabotropic glutamate receptor 5 (mGLUR5) levels. Double immunostaining for NMDAR and mGLUR5 showed that these receptors lose colocalization on the cell membrane in neurons treated with dieldrin. No changes were observed in receptor functionalities or receptor levels after 2 DIV of exposure to dieldrin. However, the increase in [Ca2+]i induced by coactivation of NMDAR and mGLUR5 was significantly reduced. Thus, a functional interaction between the two receptors seems to play an important role in glutamate-induced excitotoxicity. We confirm that permanent blockade of the GABAA receptor by this persistent pesticide triggers adaptive neuronal changes consisting of a reduction of glutamatergic neurotransmission. This might explain the cognitive and learning deficits observed in animals after chronic treatment with dieldrin.

Key Words: dieldrin; neurotoxicity; in vitro; glutamate; receptor.


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