Long-term potentiation (LTP) in the hippocampus is a model system for understanding the synaptic basis of learning and memory. We have studied the mechanism of induction of LTP using voltage-clamp techniques and confocal imaging of Ca2+ in rat hippocampal slices. In the Schaffer collateral-commissural pathway the neurotransmitter L-glutamate activates two classes of ionotropic receptor, named after the selective ligands AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) and NMDA (N-methyl-D-aspartate). During low frequency transmission the excitatory postsynaptic potential (EPSP) is mediated predominantly by AMPA receptors. NMDA receptors play a minor role because their ion channels are substantially blocked by Mg2+, and this block is intensified by GABA-mediated synaptic inhibition. During high frequency transmission the GABA-mediated inhibition is depressed, by mechanisms initiated by GABAB autoreceptors. This allows a greater contribution from the NMDA receptors, through which Ca2+ enters the dendrites of the postsynaptic neurons to initiate a cascade of biochemical processes which ultimately result in enhanced synaptic efficiency.