Department of Psychology, University of California, Los Angeles, Los Angeles, CA.
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA.
Schizophr Bull. 2017 Sep 1;43(5):1123-1133. doi: 10.1093/schbul/sbw193.
Cognitive deficits in schizophrenia have been hypothesized to reflect N-methyl-D-aspartate receptor (NMDAR) dysfunction. However, the mechanisms through which the NMDAR contributes to individual cognitive functions differ. To explore how NMDAR signaling relates to specific cognitive deficits in schizophrenia, we tested the effects of enhancing NMDAR signaling on working memory and experience-dependent plasticity using d-cycloserine (DCS). Plasticity was assessed using an EEG paradigm that utilizes high-frequency visual stimulation (HFvS) to induce neural potentiation, and 2 learning tasks, the information integration (IIT) and weather prediction (WPT) tasks. Working memory was assessed using an N-back task. Forty-five schizophrenia patients were randomized to receive a single 100 mg DCS dose (SZ-DCS; n = 24) or placebo (SZ-PLC; n = 21) in a double-blind, between-groups design. Testing occurred on a single day after placebo or DCS administration; baseline values were not obtained. DCS did not affect plasticity, as indicated by similar neural potentiation, and similar IIT and WPT learning between groups. However, among patients who successfully engaged in the working memory task (ie, performed above chance), SZ-DCS (n = 17) showed superior 2-back performance compared to SZ-PLC (n = 16). Interestingly, SZ-DCS also showed larger pre-HFvS neural responses during the LTP task. Notably, this pattern of DCS effects is the opposite of those found in our prior study of healthy adults. Results are consistent with target engagement of the NMDAR by DCS, but suggest that NMDAR signaling was not translated into synaptic plasticity changes in schizophrenia. Results highlight the importance of considering how distinct NMDAR-associated processes contribute to individual cognitive deficits in schizophrenia.
精神分裂症的认知缺陷被假设反映了 N-甲基-D-天冬氨酸受体（NMDAR）功能障碍。然而，NMDAR 促进个体认知功能的机制不同。为了探索 NMDAR 信号如何与精神分裂症的特定认知缺陷相关，我们使用 d-环丝氨酸（DCS）测试了增强 NMDAR 信号对工作记忆和经验依赖性可塑性的影响。使用利用高频视觉刺激（HFvS）诱导神经增强的 EEG 范式评估可塑性，以及 2 种学习任务，即信息整合（IIT）和天气预报（WPT）任务。使用 N 回任务评估工作记忆。45 名精神分裂症患者随机分为接受单次 100mg DCS 剂量（SZ-DCS；n = 24）或安慰剂（SZ-PLC；n = 21）的双盲、组间设计。测试在安慰剂或 DCS 给药后一天进行；未获得基线值。DCS 并未影响可塑性，表明组间神经增强和 IIT 和 WPT 学习相似。然而，在成功参与工作记忆任务（即，表现优于机会）的患者中，SZ-DCS（n = 17）与 SZ-PLC（n = 16）相比，2 回表现更好。有趣的是，SZ-DCS 在 LTP 任务期间也显示出更大的预-HFvS 神经反应。值得注意的是，这种 DCS 效应模式与我们之前对健康成年人的研究结果相反。结果与 DCS 对 NMDAR 的靶向结合一致，但表明 NMDAR 信号在精神分裂症中没有转化为突触可塑性变化。结果强调了考虑不同的 NMDAR 相关过程如何导致精神分裂症中个体认知缺陷的重要性。
