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

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

Aline Brechet, PhD Rebecca Buchert Jochen Schwenk, PhD Sami Boudkkazi, PhD Gerd Zolles, PhD Karine Siquier-Pernet Irene Schaber Wolfgang Bildl, PhD Abdelkrim Saadi Christine Bole-Feysot, PhD Patrick Nitschke Prof. Andre Reis, PhD, MD Prof. Heinrich Sticht, PhD Nouriya Al-Sannaa Prof. Arndt Rolfs, MD Akos Kulik, PhD Uwe Schulte, PhD Laurence Colleaux, PhD Rami Abou Jamra, MD Prof. Bernd Fakler, MD
July 13, 2017

Nat Commun. 2017 Jul 4;8:15910. doi: 10.1038/ncomms15910

Abstract:

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.