Long-term potentiation (LTP) is the persistent facilitation of synaptic responses induced by a brief tetanic stimulation (tetanus). From our observations and the findings of others, we hereby propose a novel hypothesis of the cellular mechanisms involved in the induction of hippocampal LTP. Quisqualate receptors are first activated during tetany and this stimulates the turnover of phosphatidyl inositol (Pl). The increased turnover activates protein kinase C and this results in the induction of LTP. The influx of Ca++ through N-methyl-D-aspartate-linked receptor mechanisms may participate in this process but is not the main factor for the activation of protein kinase C. With this hypothesis, the role of quiqualate receptors associated with the turnover of Pl is emphasized, and its relevance is discussed to the input specificity of LTP and to the modulation of LTP by certain drugs.