Loss of Frrs1l disrupts synaptic AMPA receptor function, and results in neurodevelopmental, motor, cognitive and electrographical abnormalities
Loss of Frrs1l disrupts synaptic AMPA receptor function, and results in neurodevelopmental, motor, cognitive and electrographical abnormalities
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DOI：
10.1242/dmm.036806
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发表时间：
2019-02-01
影响因子：
4.3
通讯作者：
Nolan, Patrick M.
中科院分区：
文献类型：
--
作者：
Stewart, Michelle;Lau, Petrina;Nolan, Patrick M.
人类AMPA受体相关蛋白铁螯合还原酶1样（FRRS1L）的功能丧失突变与舞蹈病、认知缺陷和癫痫性脑病等破坏性神经系统疾病有关。此外，来自过表达和离体研究的证据表明FRRS1L参与AMPA受体的生物发生，这表明谷氨酸信号传导的变化可能是这种疾病的基础。在这里，我们使用小鼠frrs11零突变体研究了该疾病的神经学和神经行为学相关因素。这项研究揭示了几种与人类患者相似的神经缺陷。我们证实，缺乏frrs11的小鼠会出现广泛的早发性运动缺陷，没有进行性的、与年龄相关的恶化。此外，无论测试环境如何，frrs11（-/-）小鼠都表现出过度活跃，表现出工作记忆缺陷和明显的睡眠碎片化。纵向脑电图（EEG）记录也显示frrs11（-/-）小鼠的EEG结果异常。对疾病病因学的平行研究发现，frrs11 -/-小鼠大脑中AMPA受体水平存在特异性缺陷，而其他几种突触成分的一般水平保持不变，突触数量没有明显改变。此外，我们确定Frrsl1缺失导致未成熟AMPA受体比例增加，这表明GLUA2（也称为GRIA2）和GLUA4（也称为GRIA4） AMPA受体蛋白的糖基化不完全。这种不完全成熟导致细胞质保留和突触后膜中特定AMPA受体水平的降低。总体而言，本研究首次在体内确定了FRRS1L功能缺失如何影响谷氨酸信号传导，并为人类多运动障碍的发生和进展提供了机制见解。
Loss-of-function mutations in a human AMPA receptor-associated protein, ferric chelate reductase 1-like (FRRS1L), are associated with a devastating neurological condition incorporating choreoathetosis, cognitive deficits and epileptic encephalopathies. Furthermore, evidence from overexpression and ex vivo studies has implicated FRRS1L in AMPA receptor biogenesis, suggesting that changes in glutamatergic signalling might underlie the disorder. Here, we investigated the neurological and neurobehavioural correlates of the disorder using a mouse Frrs1l null mutant. The study revealed several neurological defects that mirrored those seen in human patients. We established that mice lacking Frrs1l suffered from a broad spectrum of early-onset motor deficits with no progressive, age-related deterioration. Moreover, Frrs1l(-/-) mice were hyperactive, irrespective of test environment, exhibited working memory deficits and displayed significant sleep fragmentation. Longitudinal electroencephalographic (EEG) recordings also revealed abnormal EEG results in Frrs1l(-/-) mice. Parallel investigations into disease aetiology identified a specific deficiency in AMPA receptor levels in the brain of Frrs1l -/-mice, while the general levels of several other synaptic components remained unchanged, with no obvious alterations in the number of synapses. Furthermore, we established that Frrsl1 deletion results in an increased proportion of immature AMPA receptors, indicated by incomplete glycosylation of GLUA2 (also known as GRIA2) and GLUA4 (also known as GRIA4) AMPA receptor proteins. This incomplete maturation leads to cytoplasmic retention and a reduction of those specific AMPA receptor levels in the postsynaptic membrane. Overall, this study determines, for the first time in vivo, how loss of FRRS1L function can affect glutamatergic signalling, and provides mechanistic insight into the development and progression of a human hyperkinetic disorder.