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.

Impairments in remote memory caused by the lack of Type 2 IP3 receptors

“…Importantly, post hoc analysis suggested that such an effect was mostly driven by female mice. While future studies will be necessary to better understand why that might be the case, our observations add additional evidence to the growing body of literature showing a strong sex‐dependence of DAAO actions in the rodent brain (Labrie et al, ; Pritchett et al, ), as well as sex‐related differences in its expression levels in humans (Jagannath et al, ). Moreover, our results indicating that female mice are more sensitive than males to the disruption of D‐serine actions in the brain, are well aligned with previous reports showing the inability of DAAO to prevent the facilitatory actions of exogenously applied D‐serine on LTD (Zhang et al, ) or LTP (Yang et al, ) in male rodents.…”

“…Importantly, post hoc analysis suggested that such an effect was mostly driven by female mice. While future studies will be necessary to better understand why that might be the case, our observations add additional evidence to the growing body of literature showing a strong sex-dependence of DAAO actions in the rodent brain (Labrie et al, 2009;Pritchett et al, 2015), as well as sex-related differences in its expression levels in humans (Jagannath et al, 2017).…”

Metabotropic glutamate receptor 3 (mGlu3; mGluR3; GRM3) in schizophrenia: Antibody characterisation and a semi-quantitative western blot study

“…This work fostered development of mGlu2/3 agonists as potential anti-schizophrenia treatments, with a high-profile positive clinical trial for one such drug, pomaglumetad methionil (Patil et al, 2007). Though this finding was not replicated, interest in group II mGluRs in schizophrenia and as antipsychotic drug targets has persisted (Lyon et al, 2011b, Fell et al, 2012, Vinson and Conn, 2012, Lane et al, 2013, Ellaithy et al, 2015, De Filippis et al, 2015, Pritchett et al, 2015, Walker and Conn, 2015), and a recent secondary analysis of the clinical trials suggests that pomaglumetad methionil may have antipsychotic efficacy early in the disease and in patients previously exposed to D2 dopamine antagonists (Kinon et al, 2015). …”

Searching for cognitive enhancement in the Morris water maze: better and worse performance in D‐amino acid oxidase knockout (Dao−/−) mice

“…As proof of principle, Dao knockout ( Dao −/− ) mice have been generated and subjected to tests of cognition. Dao −/− mice exhibit improved spatial and non‐spatial short‐term memory (Pritchett et al ., ), and improved object recognition memory has also been reported in wild‐type (WT) rats following the administration of a DAO inhibitor (Hopkins et al ., ). However, the relationship between DAO function and associative, long‐term spatial memory is less clear.…”