Dominant mutations in the human gene GRIN2A, encoding NMDA receptor (NMDAR) subunit GluN2A, make a significant and growing contribution to the catalogue of published single-gene epilepsies. Understanding the disease mechanism in these epilepsy patients is complicated by the surprising diversity of effects that the mutations have on NMDARs. We have examined the cell-autonomous effect of five GluN2A mutations, 3 loss-of-function and 2 gain-of-function, on evoked NMDAR-mediated synaptic currents (NMDA-EPSCs) in CA1 pyramidal neurons in cultured hippocampal slices. Despite the mutants differing in their functional incorporation at synapses, prolonged NMDA-EPSC current decays (with only marginal changes in charge transfer) were a common effect for both gain- and loss-of-function mutants. Modelling NMDA-EPSCs with mutant properties in a CA1 neuron revealed that the effect of GRIN2A mutations can lead to abnormal temporal integration and spine calcium dynamics during trains of concerted synaptic activity. Investigations beyond establishing the molecular defects of GluN2A mutants are much needed to understand their impact on synaptic transmission.

中文翻译：

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人类 NMDA 受体亚基 GluN2A 的不同突变引起的常见突触表型

人类基因GRIN2A的显性突变，编码 NMDA 受体 (NMDAR) 亚基 GluN2A，对已发表的单基因癫痫目录做出了重要且不断增长的贡献。突变对 NMDAR 的影响的惊人多样性使理解这些癫痫患者的疾病机制变得复杂。我们已经检查了 5 个 GluN2A 突变、3 个功能丧失和 2 个功能获得对培养的海马切片中 CA1 锥体神经元中诱发的 NMDAR 介导的突触电流 (NMDA-EPSCs) 的细胞自主效应。尽管突变体在突触处的功能结合不同，但延长的 NMDA-EPSC 电流衰减（电荷转移只有微小的变化）是获得和丧失功能突变体的共同影响。在 CA1 神经元中对具有突变特性的 NMDA-EPSC 进行建模表明，GRIN2A突变可导致在一系列协同突触活动期间异常的时间整合和脊柱钙动力学。除了确定 GluN2A 突变体的分子缺陷之外，还需要进行调查以了解它们对突触传递的影响。