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AMPA-receptor specific biogenesis complexes control synaptic transmission and intellectual ability.

Brechet A., Buchert R., Schwenk J., Boudkkazi S., Zolles G., Siquier-Pernet K., Schaber I., Bildl W., Saadi A., Bole-Feysot C., Nitschke P., Reis A., Sticht H., Al-Sanna'a N., Rolfs A., Kulik A., Schulte U., Colleaux L., Abou Jamra R., Fakler B.

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.

Nat Commun 8:15910-15910(2017) [PubMed] [Europe PMC]

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