Domoic acid-containing toxic mussels produce neurotoxicity in neuronal cultures through a synergism between excitatory amino acids.

In 1987, an intoxication by cultured mussels produced neurological problems, such as headache, confusion, and loss of memory, particularly severe at times. Neuronal damage was found in the hippocampus and amygdala of four patients. The intoxication was attributed to the presence in mussels of domoic acid, a rare excitatory amino acid acting at the non-NMDA receptor. We now report that a domoic acid-containing mussel extract is more neurotoxic for cultured neurons than purified domoic acid. Moreover, we show that this increase in neurotoxicity is selectively due to domoic acid potentiation of the excitotoxic effect of glutamic acid and aspartic acid present in high concentrations in mussel tissue. We also show that subtoxic concentrations of domoic acid are sufficient to potentiate glutamic acid and aspartic acid neurotoxicity, and we present evidence suggesting that the neurotoxic synergism may occur through a reduction of the voltage-dependent Mg2+ block at the NMDA receptor-associated channel, following activation of non-NMDA receptors by domoic acid. Thus, based on our results, we suggest that the contemporary presence in the brain of concentrations of domoic acid insufficient alone to be toxic, together with excitatory amino acids, of endogenous and eventually of diet-related origin, may have been relevant in the occurrence of the neurological problems reported.