AMPA-type glutamate receptors (AMPARs), key elements in excitatory neurotransmission in the brain, are macromolecular complexes whose properties and cellular functions are determined by the co-assembled constituents of their proteome. Here we identify AMPAR complexes that transiently form in the endoplasmic reticulum (ER) and lack the core-subunits typical for AMPARs in the plasma membrane. Central components of these ER AMPARs are the proteome constituents FRRS1l (C9orf4) and CPT1c that specifically and cooperatively bind to the pore-forming GluA1-4 proteins of AMPARs. Bi-allelic mutations in the human FRRS1L gene are shown to cause severe intellectual disability with cognitive impairment, speech delay and epileptic activity. Virus-directed deletion or overexpression of FRRS1l strongly impact synaptic transmission in adult rat brain by decreasing or increasing the number of AMPARs in synapses and extra-synaptic sites. Our results provide insight into the early biogenesis of AMPARs and demonstrate its pronounced impact on synaptic transmission and brain function.

中文翻译：

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AMPA受体特异性生物合成复合物控制突触传递和智力。

AMPA型谷氨酸受体（AMPAR）是大脑兴奋性神经传递的关键元素，是大分子复合物，其性质和细胞功能由其蛋白质组的共组装成分决定。在这里，我们确定了在内质网（ER）中瞬时形成的AMPAR复合物，该复合物缺乏质膜中AMPAR的典型核心亚基。这些ER AMPAR的主要组成部分是蛋白质组组成部分FRRS11（C9orf4）和CPT1c，它们与AMPAR的成孔GluA1-4蛋白特异性结合。人类FRRS1L基因中的双等位基因突变显示会导致严重的智力残疾，并伴有认知障碍，语言障碍和癫痫发作。通过减少或增加突触和突触外位点中AMPAR的数量，病毒指导的FRRS11的缺失或过表达强烈影响成年大鼠脑中的突触传递。我们的结果提供了对AMPARs早期生物发生的见解，并证明了其对突触传递和脑功能的显着影响。