Smad3 inhibition enhances neurogenesis and antidepressant-like behaviors in mouse models

Abstract

Smad3 is an important effector of TGF-β function and is implicated in a variety of biological processes involving cell growth. Disruption of Smad3 has been shown to affect neurogenesis, and however, little is known about the mechanism and effect of Smad3 disruption in depressive disorder. The behavior of Smad3 deficient animals were characterized and compared to animal model of depression. Specific Smad3 inhibition in the hippocampus was assessed in a model of rodent depression. Molecular analysis on brain tissues examined the proliferation of BrdU as a marker of neurogenesis and signaling molecules relevant to the TGF-β pathway were analysed. The data showed that Smad3-deficient mice exhibited remarkable antidepressant-like behaviors and pharmacological inhibition of Smad3 had resulted in an increase of BrdU-labelled cells. Interestingly, when localized inhibition of Smad3 was performed in the rostral DG and amygdala, it was found that significant antidepressant-like responses induced by Smad3 inhibition in the DG, but not the amygdala. The results indicated that the antidepressant mechanism of Smad3 inhibition was specifically mediated by the canonical pathway, instead of the non-canonical TGF-β-TAK1-NF-κB signalling mechanism. It is further demonstrated that inhibition of neurogenesis in the hippocampus abolishes the effect of Smad3 inhibition, indicating neurogenesis-dependent mechanism of antidepressant by Smad3 function. In conclusion, inhibition of Smad3 confers resilience against stressors and it is a promising target for further investigation as a potential treatment for depression.