AbstractThe organochlorine pesticide dieldrin is a persistent organic pollutant that accumulates in the fatty tissue of living organisms. In mammals, it antagonizes the GABAA receptor, producing convulsions after acute exposure. Although accumulation in human brain has been reported, little is known about the effects of long‐term exposure to dieldrin in the nervous system. Homeostatic control of the balance between excitation and inhibition has been reported when neuronal activity is chronically altered. We hypothesized that noncytotoxic concentrations of dieldrin could decrease glutamatergic neurotransmission as a consequence of a prolonged reduction in GABAA receptor function. Long‐term exposure of primary cerebellar granule cell cultures to 3 μM dieldrin reduced the GABAA receptor function to 55% of control, as measured by the GABA‐induced 36Cl− uptake. This exposure produced a significant reduction (∼35%) of the NMDA‐induced increase in [Ca2+]i and of the [3H]MK‐801 binding, which was not accompanied by a reduction in the NMDA receptor subunit NR1, as determined by Western blot. Consistent with the decreased NMDA receptor function, dieldrin‐treated cultures were insensitive to an excitotoxic stimulus induced by exposure to high potassium. In summary, we report that the chronic reduction of GABAA receptor function induced by dieldrin decreases the number of functional NMDA receptors, which may be attributable to a mechanism of synaptic scaling. These effects could underlie neural mechanisms involved in cognitive impairment produced by low‐level exposure to dieldrin. © 2007 Wiley‐Liss, Inc.