AMPA-Receptor Specific Biogenesis Complexes Control Synaptic Transmission and Intellectual Ability
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.
Authors
- 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