NMDA receptors play crucial roles in excitatory synaptic transmission. Rare variants in GRIN2A encoding the GluN2A subunit are associated with a spectrum of disorders, ranging from mild speech and language delay to intractable neurodevelopmental disorders, including but not limited to developmental and epileptic encephalopathy. A de novo missense variant, p.Ser644Gly, was identified in a child with this disorder, and Grin2a knock-in mice were generated to model and extend understanding of this intractable childhood disease. Homozygous and heterozygous mutant mice exhibited altered hippocampal morphology at 2 weeks of age, and all homozygotes exhibited lethal tonic-clonic seizures by mid-third week. Heterozygous adults displayed susceptibility to induced generalized seizures, hyperactivity, repetitive and reduced anxiety behaviours, plus several unexpected features, including significant resistance to electrically-induced limbic seizures and to pentylenetetrazole induced tonic-clonic seizures. Multielectrode recordings of neuronal networks revealed hyperexcitability and altered bursting and synchronicity. In heterologous cells, mutant receptors had enhanced NMDA receptor agonist potency and slow deactivation following rapid removal of glutamate, as occurs at synapses. NMDA receptor-mediated synaptic currents in heterozygous hippocampal slices also showed a prolonged deactivation time course. Standard anti-epileptic drug monotherapy was ineffective in the patient. Introduction of NMDA receptor antagonists was correlated with a decrease in seizure burden. Chronic treatment of homozygous mouse pups with NMDA receptor antagonists significantly delayed the onset of lethal seizures but did not prevent them. These studies illustrate the power of using multiple experimental modalities to model and test therapies for severe neurodevelopmental disorders, while revealing significant biological complexities associated with GRIN2A developmental and epileptic encephalopathy.

中文翻译：

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模拟和治疗小鼠 GRIN2A 发育性脑病和癫痫性脑病。

NMDA 受体在兴奋性突触传递中起着至关重要的作用。编码 GluN2A 亚基的GRIN2A中的罕见变异与一系列疾病相关，从轻度言语和语言发育迟缓到顽固性神经发育障碍，包括但不限于发育性脑病和癫痫性脑病。在一名患有这种疾病的儿童中发现了一种新的错义变异 p.Ser644Gly，并生成了Grin2a敲入小鼠来模拟和扩展对这种顽固性儿童疾病的理解。纯合子和杂合子突变小鼠在两周龄时表现出海马形态的改变，所有纯合子在第三周中期都表现出致命的强直阵挛性癫痫发作。杂合子成人表现出对诱发全身性癫痫发作、多动、重复和减少焦虑行为的易感性，以及一些意想不到的特征，包括对电诱发的边缘癫痫发作和戊四唑诱发的强直阵挛癫痫发作的显着抵抗。神经元网络的多电极记录揭示了过度兴奋性以及爆发性和同步性的改变。在异源细胞中，突变受体增强了 NMDA 受体激动剂的效力，并在快速去除谷氨酸后缓慢失活，就像突触处发生的那样。杂合海马切片中 NMDA 受体介导的突触电流也显示出较长的失活时间过程。标准抗癫痫药物单一疗法对患者无效。NMDA 受体拮抗剂的引入与癫痫发作负担的减轻相关。用 NMDA 受体拮抗剂对纯合子小鼠幼崽进行长期治疗显着延迟了致命性癫痫发作的发生，但并没有阻止它们。这些研究说明了使用多种实验方式来建模和测试严重神经发育障碍疗法的力量，同时揭示了与GRIN2A发育和癫痫性脑病相关的显着生物学复杂性。