Type II TARPs are more distantly related to type I and share only some of their functional properties ( Kato et al., 2010). Recent genetic and proteomic screens have identified a number of small proteins that bind to AMPARs and are structurally unrelated to TARPs (Figure 3). These include

cornichon-2 and -3 (CNIH-2 and CNIH-3) (Schwenk et al., 2012 and Schwenk et al., 2009), CKAMP44 (von Engelhardt et al., 2010), SynDIG1 (Kalashnikova et al., 2010), selleck chemicals GSG1L (Shanks et al., 2012), and in C. elegans SOL-1 and SOL-2 ( Wang et al., 2012). The most studied of these proteins are CNIH proteins, which profoundly slow the deactivation of AMPARs in heterologous systems ( Coombs et al., 2012, Gill et al., 2012, Schwenk et al., 2009 and Shi et al., 2010). Genetic deletion of CNIH-2 and -3 together causes a profound and selective see more loss of synaptic and surface AMPARs in the hippocampus ( Herring et al., 2013). This deficit is due to the selective loss of surface GluA1-containing AMPARs (GluA1/A2 heteromers), leaving a small residual pool of synaptic GluA2/A3 heteromers. The kinetics

of AMPARs in neurons lacking CNIH-2/-3 are faster than those in WT neurons due to the fast kinetics of GluA2/A3 heteromers. The remarkably selective effect of CNIHs on the GluA1 subunit appears to be mediated by TARP γ-8, which prevents a functional association of CNIHs with non-GluA1 subunits. Surprisingly, although CNIHs strongly slow deactivation in heterologous cells, they do not directly affect the kinetics of surface neuronal AMPARs, indicating either that they dissociate from the AMPARs in the Golgi/ER akin to the chaperoning role of their yeast and Drosophila homologs or that their selective binding to surface GluA1 subunits of GluA1/A2 heteromers is functionally silent. These results point to a sophisticated

interplay between CNIHs and TARP γ-8 that dictates subunit-specific AMPAR trafficking and the strength and kinetics of synaptic AMPAR-mediated transmission. CKAMP44 is expressed at high levels in dentate granule cells where it enhances AMPAR desensitization and recovery from desensitization, Tolmetin thus impacting short-term plasticity ( von Engelhardt et al., 2010). Neuroligins (NLs) and leucine-rich repeat transmembrane proteins (LRRTMs) are postsynaptic adhesion molecules that bind to presynaptic neurexins and are involved in excitatory synapses assembly, maturation, and specification (Craig and Kang, 2007, Krueger et al., 2012 and Südhof, 2008) (Figure 3). However, recent findings indicate that both NLs and LRRTMs have more specific roles in both AMPAR trafficking and LTP. Knockdown of LRRTM1 and LRRTM2 in CA1 neurons selectively reduces AMPAR-EPSCs in the neonate (Soler-Llavina et al., 2011), although in dentate granule cells the NMDAR-EPSC is also reduced (de Wit et al., 2009).