D-Serine augments NMDA-NR2B receptor-dependent hippocampal long-term depression and spatial reversal learning
D-Serine augments NMDA-NR2B receptor-dependent hippocampal long-term depression and spatial reversal learning
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DOI：
10.1038/sj.npp.1301486
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发表时间：
2008-04-01
影响因子：
7.6
通讯作者：
Roder, John C.
中科院分区：
文献类型：
--
作者：
Duffy, Steven;Labrie, Viviane;Roder, John C.
海马长时程抑郁（LTD）对外显学习和记忆的作用了解甚少。电生理和行为学研究探讨了调节NMDA受体依赖性LTD对Morris水迷宫（MWM）空间学习的影响。NMDA受体共激动剂D-丝氨酸显著增强NR 2B依赖性LTD，但不长时程增强（LTP）或去增强，在成年野生型小鼠海马切片。外源性D-丝氨酸并没有改变MWM收购，但大大增强了随后的逆转学习的一个新的目标位置和性能在延迟匹配的地方任务。相反，NR 2B拮抗剂会破坏逆转学习并促进持续行为。内源性突触D-丝氨酸可能在LTP诱导期间饱和，因为外源性D-丝氨酸挽救了具有较低D-丝氨酸亲和力的GrinI（D481 N）突变小鼠中缺乏LTP和MWM获取。因此，D-丝氨酸可能会增强海马NR 2B依赖LTD的形式，有助于空间反转学习。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想法或行为持续为特征的精神疾病的认知灵活性。
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 GrinI(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.