Potentiation by histamine of synaptically mediated excitotoxicity in cultured hippocampal neurones: a possible role for mast cells

Excessive glutamatergic neurotransmission, particularly when mediated by th e N-methyl-D-aspartate (NMDA) subtype of glutamate receptor, is thought to underlie neuronal death in a number of neurological disorders. Histamine ha s been reported to potentiate NMDA receptor-mediated events under a variety of conditions. In the present study we have utilized primary hippocampal n eurone cultures to investigate the effect of mast cell-derived, as well as exogenously applied, histamine on neurotoxicity evoked by excessive synapti c activity. Exposure of mature cultures for 15 min to an Mg2+-free/glycine- containing buffer to trigger synaptic transmission through NMDA receptors, caused a 30-35% neuronal loss over 24 h. When co-cultured with hippocampal neurones, activated mast cells increased excitotoxic injury to 60%, an effe ct that was abolished in the presence of histaminase. Similarly, addition o f histamine during magnesium deprivation produced a concentration-dependent potentiation (+60%; EC50 : 5 muM) of neuronal death which was inhibited by sodium channel blockers and NMDA receptor antagonists, although this effec t did not involve known histamine receptors. The histamine effect was furth er potentiated by acidification of the culture medium. Cultures 'preconditi oned' by sublethal (5 min) Mg2+ deprivation exhibited less neuronal death t han controls when exposed to a more severe insult. NMDA receptor activation and the extracellular regulated kinase cascade were required for precondit ioning neuroprotection. The finding that histamine potentiates NMDA recepto r-mediated excitotoxicity may have important implications for our understan ding of conditions where enhanced glutamatergic neurotransmission is observ ed in conjunction with tissue acidification, such as cerebral ischaemia and epilepsy.