To further establish a mechanistic link between depolarizing GABA and DISC1 signaling, we co-manipulated NKCC1 and KIAA1212/Girdin, which binds directly to both DISC1 and AKT (Enomoto et al., 2009; Kim et al., 2009). KIAA1212 promotes AKT activation and is phosphorylated by AKT. shRNA-NK1 expression abolished KIAA1212-induced acceleration of dendritic growth and significantly attenuated pAKT and pS6 level increases in new neurons at 14 dpi (Figures 2I to 2K), whereas other defects were not significantly affected (Figures S2G to S2I). Taken together, these results demonstrate that DISC1 KD-induced acceleration of dendritic development of adult-born neurons not only requires, but also synergistically acts with, depolarizing GABA signaling. These results support a model that intrinsic factor DISC1 functionally gates extrinsic GABA signaling through the AKT/mTOR pathway during adult hippocampal neurogenesis (Figure 2L).
