Hippocampal SIK2 Plays A Role In The Pathophysiology Of Depression

Purpose: This study aims to explore the role of hippocampal SIK2 in the pathophysiology of depression and the antidepressant actions of fluoxetine and venlafaxine,showing that hippocampal SIK2 is a novel antidepressant target.Methods: Firstly,C57BL/6J mice were used to perform the chronic social defeat stress(CSDS)model of depression.By using various biotechnological methods including Western blotting,qRT-PCR and co-immunoprecipitation,we investigated the effects of CSDS on the hippocampal SIK2-CRTC1 pathway.Then,by using the AAV-based genetic interfering technology,CSDS model,behavioral tests and biotechnological methods(Western blotting,etc.),we explored whether hippocampal SIK2 overexpression simulates depression,inducing various depressive-like behaviors and related pathological symptoms.We also explored whether hippocampal SIK2 silencing protects against the CSDS model of depression,producing antidepressant-like actions in mice.Lastly,we investigated whether fluoxetine and venlafaxine(two antidepressants used in clinical practice)could restore the effecs of CSDS on the hippocampal SIK-CRTC1 pathway.Results: The results showed that while CSDS produced none effects on SIK1,SIK3,CRTC2 and CRTC3,it robustly increased the protein and mRNA levels of hipppocampal SIK2,and significantly decreased the protein and mRNA levels of hippocampal CRTC1.CSDS also prevented the nuclear translocation of hippocampal CRTC1,leading to remarkable decrease in nuclear CRTC1-CREB binding.Hippocampal SIK2 overexpression simulated depression,inducing not only various depressive-like behaviors(helplessness,anhedonia,social avoidance,etc.),but also down-regulated brain-derived neurotrophic factor(BDNF)signaling cascade andneurogenesis in the hippocampus.In contrast,hippocampal SIK2 silencing completely reversed the CSDS-induced effects on mice,leading to notable antidepressant actions which were mediated via regulating the function of CRTC1 and BDNF system.Besides,both fluoxetine and venlafaxine fully restored the effects of CSDS on the hippocampal SIK2-CRTC1 pathway.Conclusions: 1.Hippocampal SIK2 is involved in the pathophysiology of depression.2.Hippocampal SIK2 is a novel therapeutic target for depression.3.Hippocampal SIK2 is required for the antidepressant actions of fluoxetine and venlafaxine.