title: Activity-mediated AMPA receptor remodeling, driven by alternative splicing in the ligand-binding domain.
abstract: The AMPA-type glutamate receptor (AMPAR) subunit composition shapes synaptic transmission and varies throughout development and in response to different input patterns. Here, we show that chronic activity deprivation gives rise to synaptic AMPAR responses with enhanced fidelity. Extrasynaptic AMPARs exhibited changes in kinetics and pharmacology associated with splicing of the alternative flip/flop exons. AMPAR mRNA indeed exhibited reprogramming of the flip/flop exons for GluA1 and GluA2 subunits in response to activity, selectively in the CA1 subfield. However, the functional changes did not directly correlate with the mRNA expression profiles but result from altered assembly of GluA1/GluA2 subunit splice variants, uncovering an additional regulatory role for flip/flop splicing in excitatory signaling. Our results suggest that activity-dependent AMPAR remodeling underlies changes in short-term synaptic plasticity and provides a mechanism for neuronal homeostasis.
authors.affiliation: Neurobiology Division, MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Penn
authors.forename: Ales
authors.initials: A
authors.lastname: Balik
authors.forename: Christian
authors.initials: C
authors.lastname: Wozny
authors.forename: Ondrej
authors.initials: O
authors.lastname: Cais
authors.forename: Ingo H
authors.initials: IH
authors.lastname: Greger
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D005091:Exons / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology*; D008024:Ligands; D009924:Organ Culture Techniques; D011485:Protein Binding / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D008024:Ligands; D020033:Protein Isoforms; D018091:Receptors, AMPA; C104722:glutamate receptor ionotropic, AMPA 2