Heparin-binding growth-associated molecule (HB-GAM) is a developmentally regulated secretory protein with neurite outgrowth-promoting activity. High-frequency stimulation leading to induction of long-term potentiation (LTP) resulted in increased expression of HB-GAM in rat hippocampal area CA1. When tetanization was given in the presence of antagonists of the N-methyl-D-aspartate (NMDA) receptor and postsynaptic voltage-gated calcium channels, the mRNA level was comparable to control levels. The results indicate that high frequency stimulation inducing LTP results in calcium-dependent enhancement in HB-GAM expression, and imply a role for this extracellular protein in the modulation of synaptic function in the hippocampus.