Open AccessEffects of D‐amino acid oxidase inhibition on memory performance and long‐term potentiation in vivo
Author(s) -
Hopkins Seth C.,
Campbell Una C.,
Heffernan Michele L. R.,
Spear Kerry L.,
Jeggo Ross D.,
Spanswick David C.,
Varney Mark A.,
Large Thomas H.
Publication year - 2013
Publication title -
pharmacology research and perspectives
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.975
H-Index - 27
ISSN - 2052-1707
DOI - 10.1002/prp2.7
Subject(s) - long term potentiation , nmda receptor , excitatory postsynaptic potential , synaptic plasticity , neuroscience , in vivo , hippocampus , pharmacology , chemistry , glutamate receptor , stimulation , agonist , psychology , inhibitory postsynaptic potential , biology , receptor , biochemistry , microbiology and biotechnology
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 ( fEPSP s) were recorded before and after a theta frequency burst stimulation ( TBS ) of the S chaffer collateral pathway of the CA 1 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.