To investigate the molecular mechanism underlying DISC1 functions in adult neurogenesis, we examined AKT signaling and observed marked increase in phosphorylation levels of both AKT and its downstream effector S6 ribosomal protein (S6) in newborn dentate granule cells with DISC1 knockdown during their maturation process. Further biochemical analysis suggests a model that DISC1 directly interacts with KIAA1212 and prevents the activation of AKT signaling. The physiological significance of this model in neuronal development is supported by in vivo findings that multiple genetic means of increasing AKT signaling in newborn neurons all leads to similar developmental defects as DISC1 suppression and these defects are rescued by pharmacological inhibition of AKT downstream effector mTOR.
