According to the synaptic theory of depression, extrinsic factors such as chronic stress leads to impairments of synaptic plasticity at both morphological and functional levels, and traditional antidepressants (e.g., selective serotonin reuptake inhibitors) and new category of antidepressants (e.g., ketamine) are able to restore the synaptic plasticity via multiple intracellular pathways including AKT-mTOR1,2,81. Here, AKT1 is linked to major depressive disorder.