All drugs were applied via bath perfusion. We are grateful to Pierre Apostolides and Drs. Hai Huang, Haining Zhong, and Craig Jahr for helpful discussions and to Elizabeth Brodeen-Kuo and Drs. Kevin Bender and John Williams for advice and suggestions on the manuscript. We thank Dr. Sascha du Lac for providing GIN and GlyT2-EGFP mice. This work was supported by NIH grants RO1DC004450 (L.O.T.) and F31DC010120

(S.P.K.). “
“During biogenesis most ion channels and neurotransmitter receptors undergo regulated assembly prior to insertion into the plasma membrane. In prokaryotes many PFT�� chemical structure ion channels function as homo-oligomers, which for individual subtypes range in size from dimers to hexamers, while in eukaryotes, as a consequence find more of gene duplication, appropriate members of a diverse subunit pool must be selected to form hetero-oligomeric assemblies of restricted stoichiometry and composition. The glutamate receptor ion channels (iGluRs) which mediate excitatory synaptic transmission are important examples of the biological diversity which arose from gene duplication, and these receptors play key roles in brain development,

synaptic plasticity, motor function, information processing, and memory formation. In mammals, the diverse functional roles of iGluRs are mediated by a family of 18 genes, several of which undergo alternative splicing and mRNA editing (Traynelis et al., 2010). Genetic, biochemical, and functional studies have established that individual iGluR subunits will coassemble with members of the same functional family, but not with other subtypes, to

generate the large and diverse receptor population required for normal brain activity (Ayalon et al., 2005, Ayalon and Stern-Bach, 2001, Brose et al., 1994, Burnashev et al., 1992, Leuschner and Hoch, 1999 and Partin et al., 1993). A fundamental problem in biology is to understand the mechanisms controlling this selective assembly. The major families of iGluRs STK38 were identified by classical pre-genetic techniques, using selective ligands and functional assays, leading to identification of AMPA, kainate and NMDA receptor subtypes (Watkins and Evans, 1981). For kainate and NMDA receptors, the native receptor assemblies in vivo contain subunits encoded by two or three different gene families, several of which do not generate functional ion channels when expressed as homomeric proteins. For example, GluR5, GluR6, and GluR7 (also called GluK1, GluK2, and GluK3) can form functional homomeric ion channels in heterologous expression systems (Egebjerg et al., 1991 and Schiffer et al., 1997), but in vivo they coassemble with the KA1 and KA2 subunits from a second gene family (also called GluK4 and GluK5), which also bind glutamate, but which are functionally inactive when expressed as homomeric proteins (Herb et al., 1992 and Werner et al., 1991).