Our results reveal an intricate interplay between CNIHs and γ-8 that allow for trafficking of GluA1-containing AMPARs to synapses. Because of the selective interaction of CNIHs with GluA1, GluA1A2 heteromers are allowed to dominate the population of neuronal AMPARs in CA1 pyramidal neurons. GluA1A2 heteromers are required for LTP and display slower deactivation kinetics than GluA2A3 heteromers likely allowing for greater dendritic signal integration. Furthermore, GluA1 subunits possess an intracellular loop and long C-tails that are subject to posttranslational modification and protein interactions that have been shown to play roles in activity-dependent synaptic plasticity. It will be of interest to know if CNIHs themselves are also subject to such forms of regulation and thus contribute to activity-dependent trafficking and function of synaptic GluA1-containing AMPARs. Finally, what is the structural basis that allows CNIH and γ-8 to associate with GluA1 whereas for GluA2, γ-8 prevents a functional CNIH association? Future work toward a more complete understanding of the uniqueness of GluA1-containing AMPARs and the mechanisms that regulate their function will be invaluable to our understanding of how primary neurons of numerous brain structures communicate with one another.
