AbstractGlycoprotein nonmelanoma protein B (GPNMB, alias osteoactivin), a type I transmembrane glycoprotein, is cleaved by extracellular proteases, resulting in release of an extracellular fragment (ECF). GPNMB is widely expressed by neurons within the CNS, including the hippocampus; however, its function in the brain remains unknown. Here, we investigated the role of GPNMB in memory and learning by using transgenic (Tg) mice over‐expressing GPNMB (Tg mice on a BDF‐1 background) and ECF‐treated mice. In the hippocampus of both wild‐type and Tg mice, GPNMB was highly expressed in neurons and astrocytes. Tg mice exhibited memory improvements in two types of learning tasks but were impaired in a passive‐avoidance test. In Tg mice, the hippocampus displayed increased levels of the α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate receptor subunit GluA1. Intracerebroventricular administration of ECF (50 ng) to Institute of Cancer Research (ICR) mice also improved memory in a passive‐avoidance test and increased hippocampal GluA1 levels 24 h after treatment. In Tg mice and ECF (0.25 μg/mL)‐treated hippocampal slices, long‐term potentiation was promoted. These findings suggest that GPNMB may be a novel target for research on higher order brain functions. image Glycoprotein nonmelanoma protein B (GPNMB) is widely expressed in neurons. We investigated the role of GPNMB on memory by using transgenic mice over‐expressing GPNMB (Tg) and GPNMB extracellular fragment (ECF)‐treated mice. Both mice exhibited memory improvement. In Tg mice, protein levels of phosphorylated α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate (AMPA) receptor subunit GluA1, CaMK2 (Ca2+/calmodulin‐dependent protein kinase 2), and GSK3β (glycogen synthase kinase 3β) were increased. Tg mice and ECF‐treated hippocampus promoted LTP. These findings suggest that GPNMB might become a novel target for research on higher order brain functions.