Over the last decade, several studies have shown that high levels of polyunsaturated fatty acids (PUFAs) in the brain might limit neuronal damage in various pathological conditions. For example, in animal models of Alzheimer's disease, omega-3 type PUFAs such as docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids have been proposed to decrease both the cognitive and the cellular manifestations of premature ageing. The mechanisms by which they promote brain integrity remain to be established, and the experiments on cultured hippocampal slices described here examine the possibility that omega-3 fatty acids can modulate brain cell viability by interacting with glutamate receptors. We observed, by lactate dehydrogenase release and propidium iodide (PI) uptake, that excitotoxicity triggered by an alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor agonist was markedly reduced in hippocampal slices treated with DHA. PI uptake experiments also revealed that neuroprotection by DHA was restricted to the hippocampal CA1 region and could not be reproduced by EPA or arachidonic acid, an omega-6 PUFA. Moreover, the beneficial effect of DHA was specific to AMPA receptor stimulation, insofar as the toxicity induced by N-methyl-D-aspartate or kainate receptor agonists was not diminished by DHA preincubation. Biotinylation experiments finally indicated that the neuroprotective actions of DHA could result from down-regulation of AMPA receptors in hippocampal membranes. This investigation thus provides the first indication that a beneficial outcome of DHA on the brain could derive from specific modulation of AMPA-mediated toxicity, reinforcing the notion that dietary DHA uptake might be useful in preventing neurodegenerative diseases.