D-serine augments NMDA-NR2B receptor-dependent hippocampal long-term depression and spatial reversal learning

Neuropsychopharmacology. 2008 Apr;33(5):1004-18. doi: 10.1038/sj.npp.1301486. Epub 2007 Jul 11.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Aspartic Acid / pharmacology
  • Avoidance Learning / drug effects*
  • Avoidance Learning / physiology
  • Behavior, Animal / physiology
  • 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
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • 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


  • Carrier Proteins
  • Excitatory Amino Acid Antagonists
  • Gprin1 protein, mouse
  • NR2B NMDA receptor
  • Nerve Tissue Proteins
  • Phenols
  • Piperidines
  • Receptors, N-Methyl-D-Aspartate
  • Ro 25-6981
  • benzyloxyaspartate
  • Aspartic Acid
  • Serine