To investigate the signal mechanism of (-)clausenamide ((-)-3-hydroxy-5-(hydroxy-phenyl-methyl)-1-methyl-4-phenyl-pyrrolidin-2-one, 1) and for understanding its effect on synaptic transmission, electrophysiological recording was done for basal synaptic transmission determination. Western blot analysis was employed to examine the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and cAMP responsive element-binding protein (CREB). Immunohistochemistry and tissue in situ hybridization were applied to detect the expression of Zif268. The results showed that (-)clausenamide (1) increased the population spike of hippocampal dentate gyrus. The phosphorylation of ERK1/2 in hippocampus and cortex was increased and reached the maximum at 5 min and 30 min, respectively. (-)Clausenamide (1) promoted the phosphorylation of CREB, the downstream protein of ERK1/2. The expression of Zif268 protein and mRNA increased in both hippocampal dentate gyrus and cortex. Therefore, (-)clausenamide (1) activated the ERK1/2-CREB pathway, which may provide an explanation for its effect on potentiating synaptic transmission and improving learning and memory.