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Recent results indicate that STriatal-Enriched protein tyrosine Phosphatase (STEP) levels are regulated by brain-derived neurotrophic factor (BDNF), whose expression changes during postnatal development and aging. Here, we studied STEP ontogeny in mouse brain and changes in STEP with age with emphasis on the possible regulation by BDNF. We found that STEP expression increased during the first weeks of life, reaching adult levels by 2–3 weeks of age in the striatum and cortex, and by postnatal day (P) 7 in the hippocampus. STEP protein levels were unaffected in BDNF+/− mice, but were significantly reduced in the striatum and cortex, but not in the hippocampus, of BDNF−/− mice at P7 and P14. In adult wild-type mice there were no changes in cortical and hippocampal STEP61 levels with age. Conversely, striatal STEP levels were reduced from 12 months of age, correlating with higher ubiquitination and increased BDNF content and signaling. Lower STEP levels in older mice were paralleled by increased phosphorylation of its substrates. Since altered STEP levels are involved in cellular malfunctioning events, its reduction in the striatum with increasing age should encourage future studies of how this imbalance might participate in the aging process.STEP ontogenic profile in the striatum, cortex and hippocampus parallels that described for BDNF.BDNF−/− mice display a significant reduction of STEP levels in the striatum and cortex during early postnatal development.Adult striatal STEP levels decrease with age correlating with higher BDNF levels and increased ubiquitination.Particular STEP substrates are more phosphorylated in the striatum of older mice.