Mechanisms of domoic acid action: Glutamate receptor-mediated excitotoxicity and changes of hippocampal neurotransmission and synaptic plasticity

Domoic acid, also known as amnesiac shellfish toxin, is a potent environmental neurotoxin produced by some species of marine algae and an imposing threat to marine life and even human beings. The poorly defined mechanism of domoic acid action necessitates a better understanding of this toxin. Being a glutamate receptor agonist, it exerts powerful excitatory effects on the central nervous system (CNS) through similar mechanisms that glutamate produces excitotoxicity.; The studies described here examine possible mechanisms of DOM neurotoxicity in three different aspects. (1) The spatial and temporal involvement of different glutamate receptors and their contribution of DOM-induced neuronal death. We studied this issue by using in vitro cultured mixed cortical cells (neuron and glia) and specific glutamate receptor pharmacological agents. (2) Through direct administration of DOM into hippocampus, we correlated DOM-induced neuronal death with changes in glutamate receptor profiles using standard histological and immunohistochemical techniques. Results obtained help elucidate the mechanisms of DOM actions in its major target organ at subthreshold concentrations and will assist in risk assessment for DOM. (3) the effects of DOM exposure on synaptic plasticity changes were examined, which may have implications for DOM-induced memory deficit (anterograde amnesia). An electrophysiological approach was used to study plasticity changes of CAI field potentials after in vitro exposure to DOM in hippocampal slices.; This study provides insightful results and contributes to our current knowledge on the mechanisms of DOM neurotoxicity by showing that (1) neuronal susceptibility to DOM is a complicated outcome that is dictated by the degree of neuronal maturity, pre-conditioning to low DOM doses, and different exposure paradigms (doses vs. duration). (2) When microinjected into hippocampus, DOM produces toxic symptoms similar to those described after systemic injection. (3) Bath application of DOM to hippocampal slices caused neuronal plasticity changes in vitro, as shown by the fact that it produced a chemical form of long-term potentiation of CA1 field potential (DOM-induced long lasting enhancement, DOM-LLE) that was dependent on protein kinases (CaMKII and PKA) activity. (Abstract shortened by UMI.)...