The action of histamine on excitatory synaptic transmission in the CA1 region of the mouse hippocampus was investigated. In a medium at pH 7.4 population spikes were increased for -60 min after a brief (5 min) perfusion with histamine (5 μM) but excitatory postsynaptic potentials (EPSPs) were unaffected, as previously reported in the rat. At pH 7.0, however, a late component of extra- and intracellularly registered EPSPs was enhanced in two phases: a shorter (by 30%) and a longer lasting one (<1 h by 10%). The NMDA antagonist amino-phosphonovalerate (60 μM) blocked this late component and prevented the EPSP broadening by histamine. In some cells histamine induced burst-firing and prolonged EPSPs. The actions on EPSPs were not mediated by any of the known histamine receptors as they were not mimicked by histamine H1, H2 and H3 agonists or blocked by H1, H2 or H3 antagonists. We conclude that histamine enhances a late (NMDA) component of hippocampal EPSPs when protonization is increased by a slight shift of the pH in the acidic direction. Such shifts occur during intense nervous discharges, e.g. in epileptic tissue or following tetanic stimulation, and in hypoxic conditions.