Effects of low-dose d-serine on recognition and working memory in mice

Rationale d-Serine is an endogenous co-agonist of the N-methyl-d-aspartate (NMDA) receptor and has been suggested to improve cognitive deficits in schizophrenia. Objectives The present study investigates the effects of treatment with d-serine in mice on tasks that require recognition learning and working memory, two cognitive domains that are impaired in schizophrenia. Methods We studied the effects of various regimens of systemic administration of d-serine (50 mg/kg/day) on BALB/c mice performing object recognition, T-maze alternation, and open-field exploration tasks. For the object recognition task, we also contrasted the effects of d-serine and d-cycloserine and investigated whether d-serine could reverse alterations induced by subchronic injections of the NMDA antagonist MK-801. d-Serine levels after injections were measured by high-performance liquid chromatography. Results In the object recognition task, pre-training treatment with d-serine or d-cycloserine significantly enhanced recognition memory 24 h after training. A single administration of d-serine 30 min (but not 6 h) after training produced similar enhancement, suggesting an effect on memory consolidation. Daily treatment with d-serine enhanced both object recognition and T-maze performance over multiple days and improved short-term memory in MK-801-treated mice. d-Serine treatment did not alter open-field exploration. Behavioral effects were accompanied by increased levels of d-serine in the hippocampus of treated animals. Conclusions Our results show that treatment with d-serine can improve performance in tasks related to recognition learning and working memory, suggesting that this agent can be useful for the treatment of disorders involving declines in these cognitive domains.