Reduction of glutamatergic neurotransmission by prolonged exposure to dieldrin involves NMDA receptor internalization and metabotropic glutamate receptor 5 downregulation.
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 gamma-aminobutyric acid-A (GABA(A)) 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 ([Ca(2+)](i)) and the excitotoxicity caused by glutamate. Exposure to dieldrin for 6 DIV induced N-methyl-D-aspartate 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 [Ca(2+)](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 GABA(A) 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.
Briz
Victor
V
Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas, CSIC-IDIBAPS, Rosselló 161, E-08036 Barcelona, Spain.
Galofré
Mireia
M
Suñol
Cristina
C
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D004026:Dieldrin / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005260:Female; D018756:GABA Antagonists / Q000633:toxicity; D058787:GABA-A Receptor Antagonists; D005865:Gestational Age; D018698:Glutamic Acid / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010575:Pesticides / Q000633:toxicity*; D011247:Pregnancy; D064529:Receptor, Metabotropic Glutamate 5; D011963:Receptors, GABA-A / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*; D013997:Time Factors
D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; C578935:GRM5 protein, human; C578936:Grm5 protein, mouse; D010575:Pesticides; D064529:Receptor, Metabotropic Glutamate 5; D011963:Receptors, GABA-A; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D007770:L-Lactate Dehydrogenase; D004026:Dieldrin; D002118:Calcium