Duffy Steven, Labrie Viviane, Roder John C
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
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.
海马体长期抑制（LTD）对显性学习和记忆的贡献目前仍知之甚少。电生理学和行为学研究考察了调节NMDA受体依赖性LTD对莫里斯水迷宫（MWM）空间学习的影响。NMDA受体共激动剂D-丝氨酸可显著增强成年野生型小鼠海马切片中NR2B依赖性LTD，但对长期增强（LTP）或去增强作用无影响。外源性D-丝氨酸不会改变MWM的习得过程，但能显著增强随后对新目标位置的逆向学习以及在延迟位置匹配任务中的表现。相反，NR2B拮抗剂会干扰逆向学习并促进持续性行为。内源性突触D-丝氨酸可能在LTP诱导过程中达到饱和，因为外源性D-丝氨酸挽救了Grin1（D481N）突变小鼠中缺陷的LTP和MWM习得过程，这些突变小鼠对D-丝氨酸的亲和力较低。因此，D-丝氨酸可能增强了一种海马体NR2B依赖性LTD，这种LTD有助于空间逆向学习。通过增强这种形式的突触可塑性，D-丝氨酸可以改善以异常观念或行为的持续性为特征的精神疾病中的认知灵活性。
