D-serine augments NMDA-NR2B receptor-dependent hippocampal long-term depression and spatial reversal learning.
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.
Duffy
Steven
S
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada. duffy@mshri.on.ca
Labrie
Viviane
V
Roder
John C
JC
D000704:Analysis of Variance; D000818:Animals; D001224:Aspartic Acid / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects* / Q000502:physiology; D001522:Behavior, Animal / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000235:genetics / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000235:genetics; D010636:Phenols / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D012694:Serine / Q000378:metabolism / Q000494:pharmacology*; D013037:Spatial Behavior / Q000187:drug effects* / Q000502:physiology
D002352:Carrier Proteins; D018691:Excitatory Amino Acid Antagonists; C121673:Gprin1 protein, mouse; C121001:NR2B NMDA receptor; D009419:Nerve Tissue Proteins; D010636:Phenols; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; C109643:Ro 25-6981; C120673:benzyloxyaspartate; D001224:Aspartic Acid; D012694:Serine