D-Serine Augments NMDA-NR2B Receptor-Dependent Hippocampal Long-Term Depression and Spatial Reversal Learning

• Published in: Neuropsychopharmacology (New York, N.Y.) Vol. 33; no. 5; pp. 1004 - 1018
• Main Authors: DUFFY, Steven, LABRIE, Viviane, RODER, John C
• Format: Journal Article
• Language: English
• Published: New York, NY Nature Publishing 01.04.2008; Nature Publishing Group
• Subjects: Analysis of Variance; Animals; Aspartic Acid - pharmacology; Avoidance Learning - drug effects; Avoidance Learning - physiology; Behavior; Behavior, Animal - physiology; Biological and medical sciences; Carrier Proteins - genetics; Drug Interactions; Electric Stimulation - methods; Excitatory Amino Acid Antagonists - pharmacology; Hippocampus - drug effects; Hippocampus - physiology; Long-Term Synaptic Depression - drug effects; Long-Term Synaptic Depression - genetics; Long-Term Synaptic Depression - physiology; Long-Term Synaptic Depression - radiation effects; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mutation; Nerve Tissue Proteins - genetics; Phenols - pharmacology; Piperidines - pharmacology; Receptors, N-Methyl-D-Aspartate - physiology; Serine - metabolism; Serine - pharmacology; Spatial Behavior - drug effects; Spatial Behavior - physiology; Canada; NR2B receptor; Morris water maze; Serine; long-term depression; spatial reversal learning; Central nervous system; Space perception; Glutamate receptor; Encephalon; Synaptic transmission; Reversal learning; Aminoacid; Synaptic plasticity; Synaptic depression; Perceptive learning; NMDA receptor; Hippocampus; Biological receptor; long-term potentiation
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/sj.npp.1301486

The contributions of hippocampal long-term depression (LTD) to explicit learning and memory are poorly understood. Electrophysiological and behavioral studies examined the effects of modulating NMDA receptor-dependent LTD on spatial learning in the Morris water maze (MWM). The NMDA receptor co-agonist D-serine substantially enhanced NR2B-dependent LTD, but not long-term potentiation (LTP) or depotentiation, in hippocampal slices from adult wild type mice. Exogenous D-serine did not alter MWM acquisition, but substantially enhanced subsequent reversal learning of a novel target location and performance in a delayed-matching-to-place task. Conversely, an NR2B antagonist disrupted reversal learning and promoted perseveration. Endogenous synaptic D-serine likely saturates during LTP induction because exogenous D-serine rescued deficient LTP and MWM acquisition in Grin1(D481N) mutant mice having a lower D-serine affinity. Thus, D-serine may enhance a form of hippocampal NR2B-dependent LTD that contributes to spatial reversal learning. By enhancing this form of synaptic plasticity, D-serine could improve cognitive flexibility in psychiatric disorders characterized by perseveration of aberrant ideation or behaviors.