title: d-amino acid oxidase knockout (Dao(-/-) ) mice show enhanced short-term memory performance and heightened anxiety, but no sleep or circadian rhythm disruption.
abstract: d-amino acid oxidase (DAO, DAAO) is an enzyme that degrades d-serine, the primary endogenous co-agonist of the synaptic N-methyl-d-aspartate receptor. Convergent evidence implicates DAO in the pathophysiology and potential treatment of schizophrenia. To better understand the functional role of DAO, we characterized the behaviour of the first genetically engineered Dao knockout (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 in Dao(-/-) 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 of DAO with enhanced cognitive performance. Our results have implications for the development of DAO inhibitors as therapeutic agents.
authors: Nuffield Department of Clinical Neurosciences (Nuffield Laboratory of Ophthalmology), John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK.
authors: David
authors: D
authors: Pritchett
authors: Sibah
authors: S
authors: Hasan
authors: Shu K E
authors: SK
authors: Tam
authors: Sandra J
authors: SJ
authors: Engle
authors: Nicholas J
authors: NJ
authors: Brandon
authors: Trevor
authors: T
authors: Sharp
authors: Russell G
authors: RG
authors: Foster
authors: Paul J
authors: PJ
authors: Harrison
authors: David M
authors: DM
authors: Bannerman
authors: Stuart N
authors: SN
authors: Peirson
mesh_terms: D000818:Animals; D001007:Anxiety / Q000378:metabolism* / Q000503:physiopathology; D001362:Avoidance Learning; D002940:Circadian Rhythm; D003605:D-Amino-Acid Oxidase / Q000235:genetics / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D008297:Male; D018782:Maze Learning; D008570:Memory, Short-Term; D051379:Mice; D012890:Sleep
chemical_list: C485958:Dao1 protein, mouse; D003605:D-Amino-Acid Oxidase
keywords: N-methyl-d-aspartate receptor; d-serine; glutamate; preclinical model; schizophrenia