Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Carrer Rosselló 149, 08036, Barcelona, Spain.
Department of Child and Adolescent Psychiatry and Psychology, 2017SGR881, CIBERSAM, Institute Clinic of Neurosciences, Hospital Clínic, Carrer Villarroel 170, 08036, Barcelona, Spain.
Nat Commun. 2020 Aug 25;11(1):4250. doi: 10.1038/s41467-020-18033-3.
A mechanistic understanding of core cognitive processes, such as working memory, is crucial to addressing psychiatric symptoms in brain disorders. We propose a combined psychophysical and biophysical account of two symptomatologically related diseases, both linked to hypofunctional NMDARs: schizophrenia and autoimmune anti-NMDAR encephalitis. We first quantified shared working memory alterations in a delayed-response task. In both patient groups, we report a markedly reduced influence of previous stimuli on working memory contents, despite preserved memory precision. We then simulated this finding with NMDAR-dependent synaptic alterations in a microcircuit model of prefrontal cortex. Changes in cortical excitation destabilized within-trial memory maintenance and could not account for disrupted serial dependence in working memory. Rather, a quantitative fit between data and simulations supports alterations of an NMDAR-dependent memory mechanism operating on longer timescales, such as short-term potentiation.
对核心认知过程（如工作记忆）的机制理解对于解决大脑疾病中的精神症状至关重要。我们提出了一种与两种症状相关的疾病的综合心理物理学和生物物理学解释，这两种疾病都与 NMDAR 功能低下有关：精神分裂症和自身免疫性抗 NMDAR 脑炎。我们首先在延迟反应任务中量化了共享工作记忆的改变。在两个患者组中，尽管记忆精度得到了保留，但我们报告了先前刺激对工作记忆内容的影响明显降低。然后，我们在额皮质微电路模型中模拟了 NMDAR 依赖性突触改变的这种发现。皮层兴奋的变化破坏了试验内记忆的维持，并且不能解释工作记忆中序列相关性的破坏。相反，数据和模拟之间的定量拟合支持在更长时间尺度上操作的 NMDAR 依赖性记忆机制的改变，例如短期增强。
