In order to examine the role of the mTOR pathway in the IL cortex as a neurobiological substrate in MDD, we evaluated in this study the effects of the mTOR knockdown in mouse IL cortex on the anxious- and depressive-like behavior, the expression of synaptic plasticity markers as the brain-derived neurotrophic factor (BDNF) using in situ hybridization, and used in vivo microdialysis to explore the evoked adaptive changes in cortico–subcortical circuits leading to the emergence of a depressive-like phenotype. Here, BDNF is linked to major depressive disorder.