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

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Brechet, Aline | Buchert, Rebecca | Schwenk, Jochen | Boudkkazi, Sami | Zolles, Gerd | Siquier-Pernet, Karine | Schaber, Irene | Bildl, Wolfgang | Saadi, Abdelkrim | Bole-Feysot, Christine | Nitschke, Patrick | Reis, André | Sticht, Heinrich | Al-Sanna’a, Nouriya | Rolfs, Arndt | Kulik, Akos | Schulte, Uwe | Colleaux, Laurence | Abou Jamra, Rami | Fakler, Bernd

Edité par CCSD ; Nature Publishing Group -

International audience. AMPA-type glutamate receptors (AMPARs), key elements in excitatory neuro-transmission 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.

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