Ribosomal protein S6 kinase 1 signaling in prefrontal cortex controls depressive behavior.
Current treatments for major depressive disorder (MDD) have a time lag and are ineffective for a large number of patients. Development of novel pharmacological therapies requires a comprehensive understanding of the molecular events that contribute to MDD pathophysiology. Recent evidence points toward aberrant activity of synaptic proteins as a critical contributing factor. In the present studies, we used viral-mediated gene transfer to target a key mediator of activity-dependent synaptic protein synthesis downstream of mechanistic target of rapamycin complex 1 (mTORC1) known as p70 S6 kinase 1 (S6K1). Targeted delivery of two mutants of S6K1, constitutively active or dominant-negative, to the medial prefrontal cortex (mPFC) of rats allowed control of the mTORC1/S6K1 translational pathway. Our results demonstrate that increased expression of S6K1 in the mPFC produces antidepressant effects in the forced swim test without altering locomotor activity. Moreover, expression of active S6K1 in the mPFC blocked the anhedonia caused by chronic stress, resulting in a state of stress resilience. This antidepressant response was associated with increased neuronal complexity caused by enhanced S6K1 activity. Conversely, expression of dominant-negative S6K1 in the mPFC resulted in prodepressive behavior in the forced swim test and was sufficient to cause anhedonia in the absence of chronic stress exposure. Together, these data demonstrate a critical role for S6K1 activity in depressive behaviors, and suggest that pathways downstream of mTORC1 may underlie the pathophysiology and treatment of MDD.
Laboratory of Molecular Psychiatry, Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, CT 06508.
Jason M
JM
Dwyer
Laboratory of Molecular Psychiatry, Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, CT 06508.
Jaime G
JG
Maldonado-Avilés
Laboratory of Molecular Psychiatry, Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, CT 06508.
Ashley E
AE
Lepack
Laboratory of Molecular Psychiatry, Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, CT 06508.
Ralph J
RJ
DiLeone
Laboratory of Molecular Psychiatry, Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, CT 06508 ronald.duman@yale.edu.
Ronald S
RS
Duman
D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use; D001522:Behavior, Animal; D003865:Major Depressive Disorder / Q000378:metabolism*; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic; D007649:Ketamine / Q000737:chemistry; D008297:Male; D018782:Maze Learning; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D017397:Prefrontal Cortex / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D020123:Sirolimus / Q000737:chemistry; D013550:Swimming
D000928:Antidepressive Agents; D007649:Ketamine; D019893:Ribosomal Protein S6 Kinases; C526901:Rps6kb1 protein, rat; D020123:Sirolimus
antidepressant; prefrontal cortex; rapamycin; synapse; translation