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

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