AMPA-receptor specific biogenesis complexes control synaptic transmission and intellectual ability.
Aline BrechetRebecca BuchertJochen SchwenkSami BoudkkaziGerd ZollesKarine Siquier-PernetIrene SchaberWolfgang BildlAbdelkrim SaadiChristine Bole-FeysotPatrick NitschkeAndré ReisHeinrich StichtNouriya Al-Sanna'aArndt RolfsAkos KulikUwe SchulteLaurence ColleauxRami Abou JamraBernd FaklerPublished in: Nature communications (2017)
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.
Keyphrases
- endoplasmic reticulum
- intellectual disability
- cognitive impairment
- prefrontal cortex
- autism spectrum disorder
- white matter
- resting state
- cell proliferation
- transcription factor
- breast cancer cells
- cerebral ischemia
- functional connectivity
- genome wide
- gene expression
- early onset
- induced pluripotent stem cells
- multiple sclerosis
- blood brain barrier
- young adults
- pluripotent stem cells