Okimura T, Tanaka S, Maeda T, Kato M, Mimura M
Department of Neuropsychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Department of Information and Communication Sciences, Sophia University, 7-1 Kioicho, Chiyoda-ku, Tokyo 102-8554, Japan.
Neuroscience. 2015 Jun 4;295:80-9. doi: 10.1016/j.neuroscience.2015.03.039. Epub 2015 Mar 24.
Working memory (WM) impairment has received attention as a behavioral characteristic of schizophrenia. Neurobiological studies have led to the hypothesis that a deficit in dopamine transmission through D1 receptors in the prefrontal cortex (PFC) is associated with WM impairment in schizophrenia. However, empirical approaches that aim to clarify the nature of the impairment and its underlying mechanism are difficult to enact, especially in unmedicated patients. By contrast, computational approaches using biologically plausible models have formed a powerful theoretical framework for the study of WM impairment in schizophrenia. This article attempts to directly connect neurobiological findings to the neuropsychological behaviors present in patients with schizophrenia. Using a biologically plausible prefrontal cortical circuit model, we simulated sustained activity during a simultaneous, multi-target WM task. We subsequently analyzed how dopaminergic modulation via D1 receptor activation alters the capacity and precision of WM and investigated the underlying mechanism. Hypodopaminergic modulation resulted in imprecision and a reduced capacity in WM primarily due to decreased N-methyl-d-aspartate (NMDA) conductance. Increasing NMDA conductance ameliorated both impairments. These results account for the mechanism that underlies WM impairments in schizophrenia and provide a theoretical basis for combination therapy with antipsychotic drugs and drugs that enhance NMDA receptor function, which is expected to be effective for the treatment of WM impairments in these patients.
工作记忆（WM）损害作为精神分裂症的一种行为特征已受到关注。神经生物学研究提出了这样的假说：前额叶皮质（PFC）中通过D1受体的多巴胺传递缺陷与精神分裂症的WM损害有关。然而，旨在阐明这种损害的本质及其潜在机制的实证方法很难实施，尤其是在未用药的患者中。相比之下，使用具有生物学合理性模型的计算方法为研究精神分裂症的WM损害形成了一个强大的理论框架。本文试图将神经生物学发现与精神分裂症患者中存在的神经心理学行为直接联系起来。使用一个具有生物学合理性的前额叶皮质回路模型，我们模拟了在同时进行的多目标WM任务期间的持续活动。我们随后分析了通过D1受体激活的多巴胺能调制如何改变WM的容量和精度，并研究了潜在机制。多巴胺能调制不足主要由于N-甲基-D-天冬氨酸（NMDA）电导降低导致WM出现不精确和容量降低。增加NMDA电导可改善这两种损害。这些结果解释了精神分裂症中WM损害的潜在机制，并为抗精神病药物与增强NMDA受体功能的药物联合治疗提供了理论基础，预计这种联合治疗对这些患者的WM损害治疗有效。
