Behavioural Brain Research 217 (2011) 81–87 Contents lists available at ScienceDirect Behavioural Brain Research journal homepage: www.elsevier.com/locate/bbr Research report Behavioral characterization of a mutant mouse strain lacking d-amino acid oxidase activity Min Zhang a,∗ , Michael E. Ballard a,1 , Ana M. Basso a , Natalie Bratcher a , Kaitlin E. Browman a , Pete Curzon a , Ryuichi Konno c , Axel H. Meyer b , Lynne E. Rueter a a Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park IL 60064, USA b Abbott GmbH & CoKG, Knollstr.50, 67061 Ludwigshafen, Germany c Center for Medical Science, International University of Health and Welfare, Ohtawara, Tochigi 324-8501, Japan article info Article history: Received 8 October 2009 Received in revised form 14 September 2010 Accepted 24 September 2010 Available online 7 October 2010 Keywords: d-serine d-amino acid oxidase NMDA Prepulse inhibition Cognition Anxiety DAO mutants abstract d-amino acid oxidase (DAO), an enzyme that degrades d-serine, has been suggested as a susceptibility factor for schizophrenia. Here we sought to understand more about the behavioral consequence of lack- ing DAO and the potential therapeutic implication of DAO inhibition by characterizing a mouse strain (ddY/DAO - ) lacking DAO activity. We found that the mutant mice showed enhanced prepulse inhibition responses (PPI). Intriguingly, DAO-/- mice had increased sensitivity to the PPI-disruptive effect induced by the competitive NMDA antagonist, SDZ 220-581. In the 24-h inhibitory avoidance test, DAO-/- mice were not different from DAO+/+ mice during the recall. In Barnes Maze, we found that DAO-/- mice had a shortened latency to enter the escape tunnel. Interestingly, although these mice were hypoactive when tested in a protected open field, they showed a profound increase of activity on the edge of the unprotected open field of the Barnes Maze even with the escape tunnel removed. This increased edge activity does not appear to be related to a reduced level of anxiety given that there were no significant genotype effects on the measures of anxiety-like behaviors in two standard animal models of anxiety, elevated plus maze and novelty suppressed feeding. Our data suggest that DAO-/- mice might have altered functioning of NMDARs. However, these results provide only modest support for manipulations of DAO activity as a potential therapeutic approach to treat schizophrenia. © 2010 Elsevier B.V. All rights reserved. 1. Introduction A unique feature of N-methyl-d-aspartate (NMDA) receptors (NMDAR) is that the channel only operates when both the glutamate- and glycine-site are occupied [5]. d-serine has been rec- ognized as a major endogenous ligand acting as a co-agonist at the glycine site of NMDAR [10,19]. d-serine is mainly synthesized in glial cells [29,30]. The observations that d-serine-containing astro- cytes ensheathe NMDA-bearing neurons and that levels of d-serine parallel the distribution of NMDAR suggest that d-serine plays an important role in modulating NMDA-mediated signaling via a glial- neuronal interaction [25]. D-serine has recently drawn significant attention in the field of schizophrenia. Based on the NMDAR hypofunction theory of schizophrenia [14,22], it has been proposed that enhancing NMDAR function would have therapeutic potential. This has been tested ∗ Corresponding author. Tel.: +1 847 9381016, fax: +1 847 9380072. E-mail address: min.zhang@abbott.com (M. Zhang). 1 Note: Michael E. Ballard is now at Department of Psychiatry, University of Chicago, Chicago, IL 60637, USA. in the clinic with d-serine, glycine, d-cycloserine and sarcosine [3,8,12,13,27]. Although results are not consistent, the therapeutic benefits on schizophrenia have been reported when these agents were used as add-on therapy to antipsychotics. These clinical proof-of-concept studies have provoked drug discovery efforts for novel antipsychotics with mechanisms to enhance glycine and d- serine activity in the brain. One approach to increase d-serine is to interfere with the metabolism or re-uptake of these amino acids. Inhibiting d-amino acid oxidase (DAO), an enzyme responsible for degrading d-serine, has been proposed as one of the approaches to enhance d-serine in the brain. Several genetic linkage studies have shown an association of schizophrenia with single nucleotide polymorphisms in DAO and its activator (DAOA) [4,6,26], although contradictory results have also been reported [26]. A mouse strain (ddY/DAO - ) [15] has been identified lacking the activity of DAO due to a natural single point mutation (G181R) in DAO [24]. The mutant mice have been shown to have elevated levels of d-serine in the brain, serum, spinal cord and some periph- eral organs [9,20,28]. As expected, NMDAR-mediated excitatory postsynaptic currents recorded from spinal cord dorsal horn neu- rons were significantly enhanced in DAO mutants [28]. The ability of d-serine to modulate NMDAR function is further supported by 0166-4328/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.bbr.2010.09.030