Study timelines. Study 1 consisted of a long-term oral memantine treatment in which Ts65Dn mice and normosomic controls (NS) received memantine (20 mg/kg) for 6 months, beginning at 4 months of age. Mice from Study 1 were first tested on a 3-day win-stay RA maze at 8.5 months of age. Following spatial memory testing, the mice underwent a series of four weekly NOR testing sessions. Prior to the 3rd NOR testing session, mice that had previously received memantine were switched to control fluids, such that the 3rd session occurred with mice “off” treatment. Following this session, mice were returned to their treatments for session 4. Study 2 evaluated the effects of acute memantine administration on recognition memory in Ts65Dn mice, as naïve Ts65Dn mice received acute memantine injections (10 mg/kg, i.p.) immediately prior to NOR training and testing periods.