d‐amino acid oxidase knockout (Dao−/−) mice show enhanced short‐term memory performance and heightened anxiety, but no sleep or circadian rhythm disruption

Abstractd‐amino acid oxidase (DAO,DAAO) is an enzyme that degradesd‐serine, the primary endogenous co‐agonist of the synapticN‐methyl‐d‐aspartate receptor. Convergent evidence implicatesDAOin the pathophysiology and potential treatment of schizophrenia. To better understand the functional role ofDAO, we characterized the behaviour of the first genetically engineeredDaoknockout (Dao−/−) mouse. Our primary objective was to assess both spatial and non‐spatial short‐term memory performance. Relative to wildtype (Dao+/+) littermate controls,Dao−/−mice demonstrated enhanced spatial recognition memory performance, improved odour recognition memory performance, and enhanced spontaneous alternation in the T‐maze. In addition,Dao−/−mice displayed increased anxiety‐like behaviour in five tests of approach/avoidance conflict: the open field test, elevated plus maze, successive alleys, light/dark box and novelty‐suppressed feeding. Despite evidence of a reciprocal relationship between anxiety and sleep and circadian function in rodents, we found no evidence of sleep or circadian rhythm disruption inDao−/−mice. Overall, our observations are consistent with, and extend, findings in the natural mutant ddY/Dao−line. These data add to a growing body of preclinical evidence linking the inhibition, inactivation or deletion ofDAOwith enhanced cognitive performance. Our results have implications for the development ofDAOinhibitors as therapeutic agents.