Chunk #23 — RESULTS — Rescue of developmental defects of new neurons from DISC1 knockdown and KIAA1212 overexpression by pharmacological inhibition of mTOR, but not by inhibition of GSK3β
AKT signaling regulates cellular responses in neurons through a number of downstream effectors, including activation of mTOR pathway and inhibition of GSK3β (Manning and Cantley, 2007). Given the increased mTOR signaling as shown by the elevated pS6 levels in newborn neurons expressing DISC1-shRNA (Figure 1D) or KIAA1212 (Figure 6B), we first examined the effect of pharmacological inhibition of mTOR with rapamycin (Figure 6A). The effectiveness of in vivo application of rapamycin was confirmed by Western Blot analysis of pS6 levels in various brain tissues from injected animals (Figure S7) and by immunostaining of pS6 in GFP+ neurons expressing DISC1-shRNA or KIAA1212 in the adult brain (Figure 6B). Interestingly, application of rapamycin completely rescued defects of new neurons with DISC1 knockdown or KIAA1212 overexpression, including soma size, number of primary dendrites, total dendritic length and complexity (Figures 6C to 6G). On the other hand, rapamycin has no significant effects on both pS6 levels and morphogenesis of control GFP+ newborn neurons (Figures 6B to 6G). These results indicate that mTOR is a major downstream mediator of DISC1-dependent regulation of AKT signaling in development of newborn neurons in the adult brain.
