The above results provide an explanation for the paradox that, while all CNIH-2 binding sites of native AMPARs seem to be occupied, the kinetics of neuronal AMPARs are fast. That is, under normal conditions γ-8 prevents a functional association of CNIH-2/-3 to GluA2 and thus prevents the expected slowing of GluA1A2 heteromers. If this model is correct and CNIH proteins are able to associate with AMPARs on the surface then deleting γ-8 should cause a marked slowing in mEPSCs. However, while we confirmed a reduction in mEPSC amplitude in γ-8 KO mice (Figure 7A), no effect on mEPSC decay was observed (Figure 7B) (Rouach et al., 2005). One explanation for this might be that CNIH-2 is expressed at severely reduced levels in γ-8 KO mice (Figure 5E) (Kato et al., 2010a). Therefore, we expressed CNIH-2 in slice cultures made from γ-8 KO mice and found that CNIH-2 not only rescued the amplitude of the AMPAR-mEPSCs (Figure 7A), but also markedly slowed mEPSC responses, such that the kinetics were considerably slower than what is seen in wild-type neurons or when CNIH-2
