Effects of D-amino acid oxidase inhibition on memory performance and long-term potentiation in vivo
Open accessAbstract
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.
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Inhibition of d-amino acid oxidase through d-serine modulation augmented NMDA-R-mediated LTP in the hippocampus ex vivo and improved long-term NOP memory in vivo.
“inhibition of d-amino acid oxidase through d-serine modulation, augmented NMDA-R-mediated long-term potentiation (LTP) in the hippocampus ex vivo and improved long-term NOP memory in vivo”
From The medial prefrontal cortex - hippocampus circuit that integrates information of object, place and time to construct episodic memory in rodents: Behavioral, anatomical and neurochemical properties (2020) · cites this paper as Hopkins et al., 2013
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- Authors
- Hopkins, S. C., Campbell, U. C., Heffernan, M. L. R., Spear, K. L., Jeggo, R. D., Spanswick, D. C., Varney, M. A., & Large, T. H.
- Affiliations
- Sunovion (United States) (US)
- Neurosolutions Ltd. Coventry U.K
- University of Warwick (GB)
- Corresponding author
- Hopkins, Seth C.
- Venue
- Pharmacology Research & Perspectives
- Publisher
- Wiley
- Published
- 2013-10
- Volume
- 1
- Issue
- 1
- Pages
- e00007-e00007
- ISSN
- 2052-1707 (ISSN-L)
- PMC
- PMC4184572
- OpenAlex
- W2117830260
- Cited by
- 34
- References
- 31
- Citations by year
- 2026: 3 · 2024: 3 · 2023: 2 · 2022: 3 · 2021: 1 · 2020: 5 · 2019: 3 · 2018: 2 · 2017: 3 · 2016: 4 · 2015: 2 · 2014: 1 · 2013: 1
- FWCI
- 1.47
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Pharmacology Research & Perspectives (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Warwick Research Archive Portal (University of Warwick) (acceptedVersion)
- Funders
- Sunovion Pharmaceuticals Inc.
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- D-serine, NMDA receptor, long-term potentiation, memory consolidation, contextual fear conditioning, novel object recognition, sun, D-cycloserine, hippocampus, synaptic plasticity, cerebellum
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