In contrast to marked effects of KIAA1212 overexpression, we did not observe obvious developmental defects in newborn with KIAA1212 knockdown in the adult brain using the “single-cell genetic” approach with multiple shRNAs (Figure S9). Because of a very low basal level of AKT activation during development of immature neurons in the adult brain (Figure 1), such manipulation may lead to subtle changes that escaped detection in our experimental system. The lack of apparent KIAA1212 lost-of-function phenotypes and a low basal level of AKT phosphorylation in newborn neurons in the adult brain further support a critical role of endogenous DISC1 in preventing KIAA1212-induced activation of AKT. This result is also consistent with our previous finding that overexpression of DISC1, while rescued DISC1 knockdown defects, did not lead to detectable phenotypes in morphogenesis or positioning of newborn neurons by itself (Duan et al., 2007). In addition, pharmacological inhibition of AKT downstream target mTOR by rapamycin has little effects on normal newborn neurons in the adult dentate gyrus (Figure 6). Consistent with this finding, rapamycin was shown to exhibit little effect on normal
