The effect of β-amyloid on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor-mediated glutamatergic excitatory postsynaptic currents measured with whole-cell voltage-clamp techniques, was investigated in the rat dentate gyrus in vitro. Application of β-amyloid (1–40) by extracellular perfusion (200 nM) or intracellularly via the recording pipette (100 nM) resulted in a gradual enhancement of the NMDA receptor-mediated synaptic currents which did not reverse on washout. Basal AMPA receptor-mediated transmission, resting membrane potential or input resistance of the granule cells did not change. These results provide direct evidence that β-amyloid selectively interacts with the potentially neurotoxic NMDA receptor via a postsynaptic site. It is proposed that this action may help explain the synaptic changes seen in Alzheimer's disease.