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.
Highlights
N-methyl-D-aspartate receptor (NMDAR) activation initiates a cascade of signaling events that can lead to increases in synaptic strength
To determine if these effects of SUN on memory performance corresponded to an effect of D-amino acid oxidase (DAAO) inhibition on changes in hippocampal synaptic plasticity, we developed an in vivo long-term potentiation (LTP) paradigm sensitive to increases in NMDA receptor function
By addressing NMDAR hypofunction, DAAO is a therapeutic target for the treatment of schizophrenia, especially for improving cognitive and negative symptoms
Summary
N-methyl-D-aspartate receptor (NMDAR) activation initiates a cascade of signaling events that can lead to increases in synaptic strength. NMDA receptors play a unique role in our understanding of associative memory formation due to their biophysical requirements for activation. The multiple requirements of occupancy by two agonists (glutamate on NR2 subunits, D-serine or glycine on NR1 subunits) plus membrane depolarization to relieve Mg2+ block of the channel pore, tightly couple the coincidence of multiple extracellular signals to NMDA receptor-mediated intracellular signaling responses. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
