Genetic inactivation of D-amino acid oxidase enhances extinction and reversal learning in mice. Learn Mem

Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto M5G 1X5, Canada.
Learning & memory (Cold Spring Harbor, N.Y.) (Impact Factor: 3.66). 02/2009; 16(1):28-37. DOI: 10.1101/lm.1112209
Source: PubMed


Activation of the N-methyl-D-aspartate receptor (NMDAR) glycine site has been shown to accelerate adaptive forms of learning that may benefit psychopathologies involving cognitive and perseverative disturbances. In this study, the effects of increasing the brain levels of the endogenous NMDAR glycine site agonist D-serine, through the genetic inactivation of its catabolic enzyme D-amino acid oxidase (DAO), were examined in behavioral tests of learning and memory. In the Morris water maze task (MWM), mice carrying the hypofunctional Dao1(G181R) mutation demonstrated normal acquisition of a single platform location but had substantially improved memory for a new target location in the subsequent reversal phase. Furthermore, Dao1(G181R) mutant animals exhibited an increased rate of extinction in the MWM that was similarly observed following pharmacological administration of D-serine (600 mg/kg) in wild-type C57BL/6J mice. In contextual and cued fear conditioning, no alterations were found in initial associative memory recall; however, extinction of the contextual fear memory was facilitated in mutant animals. Thus, an augmented level of D-serine resulting from reduced DAO activity promotes adaptive learning in response to changing conditions. The NMDAR glycine site and DAO may be promising therapeutic targets to improve cognitive flexibility and inhibitory learning in psychiatric disorders such as schizophrenia and anxiety syndromes.

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    • "However, many studies during the last 15 years have shown that D-serine, an unusual amino acid synthesized in the brain by serine racemase (SR; Campanini et al., 2013) and degraded by the peroxysomal flavoprotein D-amino acid oxidase (DAAO; Sacchi et al., 2012), is the main coagonist of synaptic NMDARs in various brain areas (Martineau et al., 2006; Wolosker, 2011; Billard, 2012; Van Horn et al., 2013). Accordingly, D-serine is a physiological modulator of many NMDAR-dependent functions, including brain development (Kim et al., 2005), synaptic transmission and long-term synaptic plasticity (Figure 1; Mothet et al., 2000; Yang et al., 2003; Papouin et al., 2012; Li et al., 2013; Rosenberg et al., 2013), as well as learning, memory, and social interactions (Labrie et al., 2008; DeVito et al., 2011). Additionally, alterations in D-serine metabolism and extracellular levels appear to be central to several pathological states. "
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    ABSTRACT: Accumulating evidence during the last decade established that D-serine is a key signaling molecule utilized by neurons and astroglia in the mammalian central nervous system. D-serine is increasingly appreciated as the main physiological endogenous coagonist for synaptic NMDA receptors at central excitatory synapses; it is mandatory for long-term changes in synaptic strength, memory, learning, and social interactions. Alterations in the extracellular levels of D-serine leading to disrupted cell-cell signaling are a trademark of many chronic or acute neurological (i.e., Alzheimer disease, epilepsy, stroke) and psychiatric (i.e., schizophrenia) disorders, and are associated with addictive behavior (i.e., cocaine addiction). Indeed, fine tuning of the extracellular levels of D-serine, achieved by various molecular machineries and signaling pathways, is necessary for maintenance of accurate NMDA receptor functions. Here, we review the experimental data supporting the notion that astroglia and neurons use different pathways to regulate levels of extracellular D-serine.
    Frontiers in Synaptic Neuroscience 05/2014; 6:12. DOI:10.3389/fnsyn.2014.00012
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    • "As shown in Fig. 5B, basal D-serine levels in the cerebellum of DAAO-KO mice were substantially higher than those of wild-type mice. Previous studies that used other strains of mice lacking DAAO activity also had similar results (Morikawa et al., 2001; Labrie et al., 2009). In the cortex, the basal D-serine levels were nearly identical between wild-type and DAAO-KO mice. "
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    ABSTRACT: d-Amino acid oxidase (DAAO) catalyzes the oxidative deamination of d-amino acids including d-serine, a full agonist at the glycine modulatory site of the N-methyl-d-aspartate (NMDA) receptor. To evaluate the significance of DAAO-mediated metabolism in the pharmacokinetics of oral d-serine, plasma d-serine levels were measured in both wild-type mice and transgenic mice lacking DAAO. Although d-serine levels were rapidly diminished in wild-type mice (t(½) = 1.2 h), sustained drug levels over the course of 4 h (t(½) > 10 h) were observed in mice lacking DAAO. Coadministration of d-serine with 6-chlorobenzo[d]isoxazol-3-ol (CBIO), a small-molecule DAAO inhibitor, in wild-type mice resulted in the enhancement of plasma d-serine levels, although CBIO seems to have only temporary effects on the plasma d-serine levels due to glucuronidation of the key hydroxyl group. These findings highlight the predominant role of DAAO in the clearance of d-serine from the systemic circulation. Thus, a potent DAAO inhibitor with a longer half-life should be capable of maintaining high plasma d-serine levels over a sustained period of time and might have therapeutic implications for the treatment of schizophrenia.
    Drug metabolism and disposition: the biological fate of chemicals 07/2012; 40(11):2067-73. DOI:10.1124/dmd.112.046482 · 3.25 Impact Factor
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    • "A previous study reported that in wild-type mice, performance in the reversal MWM task was attributed to the capacity for cognitive flexibility; that is, the ability to simultaneously inhibit a previously acquired spatial navigation strategy and develop a new strategy. 30 In the present study, this capacity was weakened in rats of the nano-ZnO-treated group. Nano-ZnO-treated rats pertinaciously insisted on an inflexible strategy, suggesting that the memory associated with the original learning of the task stably remained in the nano-ZnO-treated rats. "
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    ABSTRACT: This study focused on the effects of zinc oxide nanoparticles (nano-ZnO) on spatial learning and memory and synaptic plasticity in the hippocampus of young rats, and tried to interpret the underlying mechanism. Rats were randomly divided into four groups. Nano-ZnO and phosphate-buffered saline were administered in 4-week-old rats for 8 weeks. Subsequently, performance in Morris water maze (MWM) was determined, and then long-term potentiation (LTP) and depotentiation were measured in the perforant pathway to dentate gyrus (DG) in anesthetized rats. The data showed that, (1) in MWM, the escape latency was prolonged in the nano-ZnO group and, (2) LTP was significantly enhanced in the nano-ZnO group, while depotentiation was barely influenced in the DG region of the nano-ZnO group. This bidirectional effect on long-term synaptic plasticity broke the balance between stability and flexibility of cognition. The spatial learning and memory ability was attenuated by the alteration of synaptic plasticity in nano-ZnO-treated rats.
    International Journal of Nanomedicine 07/2011; 6:1453-61. DOI:10.2147/IJN.S18507 · 4.38 Impact Factor
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