Selective serotonin reuptake inhibitors (SSRIs) stimulate synaptic plasticity and neurogenesis, most likely via the MAP-kinase signal transduction pathway (by phosphorilation of ERK) and by stimulating neurotrophic factors such as brain derived neurotrophic factor (BDNF) and the neuroprotective protein (Bcl-2). Using human neuroblastoma cells (SHSY5Y), we found that sertraline and its derivative, desmethylsertraline, at low concentrations (1–10 μM), induced potent neurotrophic activity. Subsequently, we have treated for 21 days young and aged mice with sertraline. Sertraline in certain doses improved significantly spatial memory learning, in both young and old mice. Sertraline treatment resulted in up-regulation of brain BDNF, phospho-ERK and Bcl-2 that may be involved in the pro-cognitive effect of sertraline.