In this study, we used a variety of approaches, including the generation of conditional KO mice for CNIH-2 and CNIH-3, to determine the role of cornichon proteins in the regulation of neuronal AMPARs. By deleting CNIHs from neurons, we reveal a critical role for these proteins in regulating AMPAR-mediated synaptic transmission, as there is a profound loss of AMPAR currents in KO neurons. We have demonstrated that under native conditions CNIH is saturating and the knock-down or KO of CNIHs is essential for studying their roles in neurons. Furthermore, we find an unanticipated subunit specificity, in that CNIH-2/-3 preferentially interact with, and functionally regulate GluA1-containing AMPARs. Strikingly, CNIH-2/-3 KO neurons phenocopy GluA1 KO neurons with respect to their current amplitudes, kinetics and synaptic plasticity. All of our findings are most consistent with a model in which the primary role of CNIH-2/-3 in CA1 pyramidal neurons is the selective trafficking of GluA1-containing receptors to synapses.
