Effects of D‐amino acid oxidase inhibition on memory performance and long‐term potentiation in vivo

Abstract

N-methyl-d-aspartate receptor (NMDAR) activation can initiate changes in synaptic strength, evident as long-term potentiation (LTP), and is a key molecular correlate of memory formation. Inhibition of d-amino acid oxidase (DAAO) may increase NMDAR activity by regulating d-serine concentrations, but which neuronal and behavioral effects are influenced by DAAO inhibition remain elusive. In anesthetized rats, extracellular field excitatory postsynaptic potentials (fEPSPs) were recorded before and after a theta frequency burst stimulation (TBS) of the Schaffer collateral pathway of the CA1 region in the hippocampus. Memory performance was assessed after training with tests of contextual fear conditioning (FC, mice) and novel object recognition (NOR, rats). Oral administration of 3, 10, and 30 mg/kg 4H-furo[3,2-b]pyrrole-5-carboxylic acid (SUN) produced dose-related and steady increases of cerebellum d-serine in rats and mice, indicative of lasting inhibition of central DAAO. SUN administered 2 h prior to training improved contextual fear conditioning in mice and novel object recognition memory in rats when tested 24 h after training. In anesthetized rats, LTP was established proportional to the number of TBS trains. d-cycloserine (DCS) was used to identify a submaximal level of LTP (5× TBS) that responded to NMDA receptor activation; SUN administered at 10 mg/kg 3–4 h prior to testing similarly increased in vivo LTP levels compared to vehicle control animals. Interestingly, in vivo administration of DCS also increased brain d-serine concentrations. These results indicate that DAAO inhibition increased NMDAR-related synaptic plasticity during phases of post training memory consolidation to improve memory performance in hippocampal-dependent behavioral tests.

d‐amino acid oxidase knockout (Dao−/−) mice show enhanced short‐term memory performance and heightened anxiety, but no sleep or circadian rhythm disruption

“…Behavioural phenotyping of these mutants has focused predominantly on tests of long‐term spatial memory; ddY/ Dao − mice show enhanced performance in the Barnes maze (Zhang et al ., ) and improved acquisition in the MWM (Maekawa et al ., ), whereas Dao1 G181R mice display enhanced MWM reversal learning (Labrie et al ., ). Enhanced long‐term memory performance has also been observed in wildtype rodents after the administration of d ‐serine or DAO inhibitors (Duffy et al ., ; Hashimoto et al ., ; Karasawa et al ., ; Smith et al ., ; Bado et al ., ; Hopkins et al ., ). Dao −/− mice demonstrate a complex behavioural phenotype in the MWM (D. Pritchett, A.M. Taylor, S.J.…”

“…To explore the functional role of DAO, behaviour has been assessed in two related mutant mouse lines that lack DAO activity, and in wildtype rodents following the administration of d ‐serine or DAO inhibitors. These models demonstrate enhanced performance in several long‐term memory paradigms, including the Barnes maze, Morris watermaze (MWM), and object recognition memory tests with long retention intervals (Maekawa et al ., ; Duffy et al ., ; Hashimoto et al ., ; Karasawa et al ., ; Labrie et al ., ; Smith et al ., ; Bado et al ., ; Zhang et al ., ; Hopkins et al ., ). Although T‐maze rewarded alternation is enhanced in wildtype mice following d ‐serine administration (Bado et al ., ), short‐term memory has yet to be assessed in a genetic mouse model lacking DAO activity.…”

D-serine plasma concentration is a potential biomarker of (R,S)-ketamine antidepressant response in subjects with treatment-resistant depression

“…A second study has identified baseline neurocognitive performance as a potential predictor of response to treatment with KET, with KET-Rs having poorer baseline neurocognitive performance (Murrough et al 2014). Since D-Ser plays a key role in long-term potentiation and NMDA-related synaptic plasticity (Henneberger et al 2010; Papouin et al 2012; Hopkins et al 2013), the higher D-Ser baseline concentrations found in KET-NRs is consistent with better neurocognitive performance in this group of patients.…”

Translating advances in the molecular basis of schizophrenia into novel cognitive treatment strategies

“…A mouse strain lacking DAAO/DAO, an enzyme involved in metabolism of D‐serine, demonstrated increased NMDA receptor transmission that was accompanied by improved spatial and non‐spatial short‐term memory (Pritchett et al, ), but no changes in spatial learning (Labrie et al , ) or long‐term spatial memory in the Morris water maze, appetitive Y‐maze task and aversive Y‐maze swim‐escape task (Pritchett et al, ). In addition, exogenous D‐serine and DAAO/DAO inhibitors each improve object recognition memory performance in rodents (Bado et al, ; Hopkins et al, ). However, Weiser et al () reported low‐dose D‐serine as an adjunct to antipsychotics to be ineffective for negative symptoms or cognitive impairment in schizophrenia; other studies have suggested that although higher‐dose D‐serine may provide additional opportunities to investigate pro‐cognitive effects in schizophrenia, nephrotoxicity is an issue for concern.…”