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谷氨酸能 N-甲基-D-天冬氨酸受体 2B 编码基因(GRIN2B)中的遗传变异对工作记忆表现期间前额叶功能的联合影响。

Combined effect of genetic variants in the GluN2B coding gene (GRIN2B) on prefrontal function during working memory performance.

机构信息

Department of Basic Medical Sciences,Neuroscience and Sensory Organs,University of Bari 'Aldo Moro',Piazza Giulio Cesare 11,70124 Bari,Italy.

出版信息

Psychol Med. 2016 Apr;46(6):1135-50. doi: 10.1017/S0033291715002639. Epub 2015 Dec 22.

Abstract

BACKGROUND

The GluN2B subunit of N-methyl-d-aspartate receptors is crucially involved in the physiology of the prefrontal cortex during working memory (WM). Consistently, genetic variants in the GluN2B coding gene (GRIN2B) have been associated with cognitive phenotypes. However, it is unclear how GRIN2B genetic variation affects gene expression and prefrontal cognitive processing. Using a composite score, we tested the combined effect of GRIN2B variants on prefrontal activity during WM performance in healthy subjects.

METHOD

We computed a composite score to combine the effects of single nucleotide polymorphisms on post-mortem prefrontal GRIN2B mRNA expression. We then computed the composite score in independent samples of healthy participants in a peripheral blood expression study (n = 46), in a WM behavioural study (n = 116) and in a WM functional magnetic resonance imaging study (n = 122).

RESULTS

Five polymorphisms were associated with GRIN2B expression: rs2160517, rs219931, rs11055792, rs17833967 and rs12814951 (all corrected p < 0.05). The score computed to account for their combined effect reliably indexed gene expression. GRIN2B composite score correlated negatively with intelligence quotient, WM behavioural efficiency and dorsolateral prefrontal cortex activity. Moreover, there was a non-linear association between GRIN2B genetic score and prefrontal activity, i.e. both high and low putative genetic score levels were associated with high blood oxygen level-dependent signals in the prefrontal cortex.

CONCLUSIONS

Multiple genetic variants in GRIN2B are jointly associated with gene expression, prefrontal function and behaviour during WM. These results support the role of GRIN2B genetic variants in WM prefrontal activity in human adults.

摘要

背景

N-甲基-D-天冬氨酸受体的 GluN2B 亚基在后前额叶皮层的工作记忆(WM)生理中起着至关重要的作用。一致地,GluN2B 编码基因(GRIN2B)中的遗传变异与认知表型有关。然而,GRIN2B 遗传变异如何影响基因表达和前额叶认知处理尚不清楚。我们使用综合评分来测试 GRIN2B 变体在健康受试者 WM 表现期间对前额叶活动的综合影响。

方法

我们计算了一个综合评分,以组合单核苷酸多态性对死后前额叶 GRIN2B mRNA 表达的影响。然后,我们在一个外周血表达研究(n=46)、一个 WM 行为研究(n=116)和一个 WM 功能磁共振成像研究(n=122)的独立健康参与者样本中计算了综合评分。

结果

五个多态性与 GRIN2B 表达相关:rs2160517、rs219931、rs11055792、rs17833967 和 rs12814951(所有校正后 p<0.05)。计算来解释它们综合效应的评分可靠地标记了基因表达。GRIN2B 综合评分与智商、WM 行为效率和背外侧前额叶皮层活动呈负相关。此外,GRIN2B 遗传评分与前额叶活动之间存在非线性关联,即高和低假定遗传评分水平都与前额叶皮层的血氧水平依赖性信号升高相关。

结论

GRIN2B 中的多个遗传变异与 WM 期间的基因表达、前额叶功能和行为联合相关。这些结果支持了 GRIN2B 遗传变异在人类成年人 WM 前额叶活动中的作用。

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