“AMPA-type glutamate receptors (AMPARs) initiate postsynaptic signaling at excitatory synapses (Traynelis et al., 2010; Trussell, 1999). Receptor desensitization can shape synaptic transmission and in turn information processing (Chen et al., 2002; Koike-Tani et al., 2008; Rozov et al.,
2001; Xu-Friedman and Regehr, 2003) as a function of the cleft glutamate transient (Cathala et al., Entinostat 2005; Jonas, 2000; Xu-Friedman and Regehr, 2003). AMPAR kinetics are tuned by the composition and alternative RNA processing of the four core subunits (GluA1–GluA4) (Geiger et al., 1995; Jonas, 2000) and by auxiliary factors (Guzman and Jonas, 2010; Jackson and Nicoll, 2011). Neurons express a variety of functionally distinct
AMPARs, which can be recruited selectively in response to different input patterns (Liu and Cull-Candy, 2000) and be targeted to specific dendritic subdomains (Bagal et al., 2005; Gardner et al., 1999; Selleck MDV3100 Tóth and McBain, 1998). However, whether assembly into distinct heteromers is modulated by activity is not known (Pozo and Goda, 2010; Turrigiano, 2008). Activity-driven remodeling of kinetically distinct receptors would permit adaptive responses to changing input patterns. The ion channel and ligand-binding domain (LBD) of the receptor feature regulatory elements at subunit interfaces introduced by alternative RNA processing (Seeburg, 1996). Q/R editing at the A2 channel pore controls Ca2+ flux and receptor tetramerization
(Greger very et al., 2003; Isaac et al., 2007), whereas the R/G editing and alternative splicing within the LBD modulate gating kinetics and subunit dimerization (Lomeli et al., 1994; Seeburg, 1996; Greger et al., 2006). Both impact on secretion of recombinant A2 from the endoplasmic reticulum (ER), where prolonging ER residence facilitates heteromeric assembly (Sukumaran et al., 2012; see also Coleman et al., 2010). Whether this mechanism contributes to the biogenesis of native AMPARs has not been addressed. Here we show that alternative splicing in the LBD is subject to regulation. Chronic reduction of activity in hippocampal slice cultures results in changes at the flip/flop (i/o) cassette. Altered RNA splicing occurs for A1 and A2 in the CA1 subfield but not in CA3, implying cell-autonomous splicing regulation. Characterization of AMPARs after activity deprivation reveals changes in pharmacology and kinetics of extrasynaptic receptors, culminating in increased response fidelity. A functional switch is also evident at CA1 synapses, which cannot be explained by a direct effect of mRNA processing (Mosbacher et al., 1994) but rather by splice variant-driven receptor remodeling.