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.
Highlights
The search for cognitive-enhancing drugs is a primary goal in industry, medicine and academia, which has enormous therapeutic relevance for numerous psychiatric and neurological disorders
It is widely acknowledged that glycine and D-serine are the primary endogenous co-agonists of extra-synaptic and synaptic N-methyl-D-aspartate receptor (NMDAR), respectively (Schell et al, 1995; Mothet et al, 2000; Oliet & Mothet, 2009; Papouin et al, 2012)
Drugs that inhibit D-amino acid oxidase (DAO), an enzyme that degrades D-serine, are under investigation as potential cognitive enhancers (Smith et al, 2010; Ferraris & Tsukamoto, 2011; Sacchi et al, 2013)
Summary
The search for cognitive-enhancing drugs is a primary goal in industry, medicine and academia, which has enormous therapeutic relevance for numerous psychiatric and neurological disorders. Drugs that inhibit D-amino acid oxidase (DAO), an enzyme that degrades D-serine, are under investigation as potential cognitive enhancers (Smith et al, 2010; Ferraris & Tsukamoto, 2011; Sacchi et al, 2013). This approach may be relevant to schizophrenia, which is thought to involve NMDAR hypofunction (Olney et al, 1999; Kantrowitz & Javitt, 2010; Marek et al, 2010; Coyle, 2012); DAO has been implicated in this hypofunction (Verrall et al 2010)
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