Growth factor-mediated signaling has emerged as an essential component of memory formation. In this study, we used a phospholipase C gamma 1 (PLC[gamma]1) binding, cell-penetrating peptide to sequester PLC[gamma]1 away from its target, the phosphotyrosine residues within the activated growth factor receptor. Peptides appear to transduce neurons but not astrocytes or oligodendrocytes. The presence of the peptides in the hippocampus during training in the Morris water maze significantly impaired long-term memory, but not memory acquisition. These results, along with previous studies on extracellular signal-regulated kinase (ERK) and phosphoinositide-3 kinase (PI3K), implicate all three key growth factor receptor-activated intracellular signaling pathways in memory storage. (Contains 4 figures.)