title: Searching for cognitive enhancement in the Morris water maze: better and worse performance in D-amino acid oxidase knockout (Dao(-/-)) mice.
abstract: A common strategy when searching for cognitive-enhancing drugs has been to target the N-methyl-d-aspartate receptor (NMDAR), given its putative role in synaptic plasticity and learning. Evidence in favour of this approach has come primarily from studies with rodents using behavioural assays like the Morris water maze. D-amino acid oxidase (DAO) degrades neutral D-amino acids such as D-serine, the primary endogenous co-agonist acting at the glycine site of the synaptic NMDAR. Inhibiting DAO could therefore provide an effective and viable means of enhancing cognition, particularly in disorders like schizophrenia, in which NMDAR hypofunction is implicated. Indirect support for this notion comes from the enhanced hippocampal long-term potentiation and facilitated water maze acquisition of ddY/Dao(-) mice, which lack DAO activity due to a point mutation in the gene. Here, in Dao knockout (Dao(-/-) ) mice, we report both better and worse water maze performance, depending on the radial distance of the hidden platform from the side wall of the pool. Dao(-/-) mice displayed an increased innate preference for swimming in the periphery of the maze (possibly due to heightened anxiety), which facilitated the discovery of a peripherally located platform, but delayed the discovery of a centrally located platform. By contrast, Dao(-/-) mice exhibited normal performance in two alternative assays of long-term spatial memory: the appetitive and aversive Y-maze reference memory tasks. Taken together, these results question the proposed relationship between DAO inactivation and enhanced long-term associative spatial memory. They also have generic implications for how Morris water maze studies are performed and interpreted.
authors.affiliation: Nuffield Department of Clinical Neurosciences (Nuffield Laboratory of Ophthalmology), John Radcliffe Hospital, University of Oxford, Oxford, UK.
authors.forename: David
authors.initials: D
authors.lastname: Pritchett
authors.affiliation: Department of Experimental Psychology, University of Oxford, Tinbergen Building, 9 South Parks Road, Oxford, OX1 3UD, UK.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Taylor
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Barkus
authors.affiliation: Pfizer Inc., Groton, CT, USA.
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Engle
authors.affiliation: Pfizer Inc., Groton, CT, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Brandon
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, UK.
authors.forename: Trevor
authors.initials: T
authors.lastname: Sharp
authors.affiliation: Nuffield Department of Clinical Neurosciences (Nuffield Laboratory of Ophthalmology), John Radcliffe Hospital, University of Oxford, Oxford, UK.
authors.forename: Russell G
authors.initials: RG
authors.lastname: Foster
authors.affiliation: Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Harrison
authors.affiliation: Nuffield Department of Clinical Neurosciences (Nuffield Laboratory of Ophthalmology), John Radcliffe Hospital, University of Oxford, Oxford, UK.
authors.forename: Stuart N
authors.initials: SN
authors.lastname: Peirson
authors.affiliation: Department of Experimental Psychology, University of Oxford, Tinbergen Building, 9 South Parks Road, Oxford, OX1 3UD, UK.
authors.forename: David M
authors.initials: DM
authors.lastname: Bannerman
mesh_terms: D000818:Animals; D003071:Cognition; D003605:D-Amino-Acid Oxidase / Q000235:genetics* / Q000378:metabolism; D005260:Female; D008297:Male; D018782:Maze Learning; D057567:Memory, Long-Term; D051379:Mice; D065852:Spatial Memory
chemical_list: C485958:Dao1 protein, mouse; D003605:D-Amino-Acid Oxidase
keywords: D-serine; N-methyl-d-aspartate receptor; glutamate; pre-clinical model; schizophrenia
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