Inhibition of Autophagy in Microglia Alters Depressive-Like Behavior via BDNF Pathway in Postpartum Depression

Abstract

Postpartum depression (PPD) is associated with mood disorders and elevated inflammation. Studies have evidenced the activation/inhibition of autophagy and excessive activation of microglia to have a close relationship with depression. C57 and microglia-specific autophagy-deficient mice (Cx3Cr1Cre/+ATG5loxp/loxp) were employed to establish the chronic unpredicted mild stress depression mice model from embryonic day 7 (E7) to embryonic day 16 (E16). Fluoxetine was administered for 3 weeks (commencing from 1 week after birth). Behavioral tests (open field, forced swimming, and sucrose preference tests) were implemented. Western blot and immunofluorescence staining were employed to assess the brain-derived neurotrophic factor (BDNF) expression level, autophagy-associated proteins, and inflammatory factors. Depressive behavior was reversed following fluoxetine treatment; this was evidenced via open field, sucrose preference, and forced swimming tests. Both BDNF and autophagy-associated proteins (ATG5, Beclin-1, and LC3II) were upregulated following fluoxetine treatment. Inflammatory factors including nuclear factor kappa B and inducible nitric oxide synthase were reduced while anti-inflammatory factor interleukin-10 (IL-10) was increased after fluoxetine treatment. Microglia-specific autophagy-deficient mice (Cx3Cr1Cre/+ATG5loxp/loxp) showed a curtailed autophagy level, higher inflammatory level, and reduced BDNF expression when compared with C57 mice. Autophagy inhibition in microglia contributes to inflammation, which further instigates PPD. Fluoxetine might mediate its antidepressant effect in PPD through the autophagic pathway while upregulating BDNF expression. In view of this, regulating BDNF in microglia is a potential novel therapy target for PPD.

BDNF‐TrkB pathway mediates antidepressant‐like roles of H2S in diabetic rats via promoting hippocampal autophagy

“…Thus, we demonstrated that H 2 S‐enhanced hippocampal autophagy in STZ‐induced diabetic rats is achieved by upregulation of BDNF. It has been reported that BDNF promotes neuron survival through improving autophagy and that fluoxetine exerts its antidepressant effect through enhancing the autophagic pathway by upregulation of the BDNF‐TrkB pathway . Therefore, our present data indicate that the contribution of the BDNF‐TrkB pathway to the antidepressant‐like roles of H 2 S in STZ‐induced diabetic rats is achieved by promoting hippocampal autophagy (Figure ).…”

“…Simultaneously, emerging evidence has indicated that exogenous H 2 S protects the heart and renal organs against ischaemic‐reperfusion injury in rats via increasing autophagy . Interestingly, it has been revealed that BDNF promotes neuron survival through improving autophagy and that fluoxetine exerts its antidepressant effect through enhancing autophagic pathway by upregulation of the BDNF‐TrkB pathway . Therefore, we would like to investigate whether the contribution of the BDNF‐TrkB pathway to antidepressant‐like effects of H 2 S in diabetic rats is achieved by enhancing hippocampal autophagy.…”

The antidepressant effects of apigenin are associated with the�promotion of autophagy via the mTOR/AMPK/ULK1 pathway

“…it is well-known that autophagy is highly associated with the pathogenesis of depressive disorder (16). autophagy can eliminate damaged organelles and proteins, and is considered to be a conserved process that regulates catabolic processes, and it contributes to the maintenance of cellular energy homeostasis and regulation of cell growth (17).…”

Autophagy-Based Hypothesis on the Role of Brain Catecholamine Response During Stress

“…This is not surprising since autophagy has been implicated in the regulation of neurogenesis, which is altered by psychological stress and represents a risk factor for the development of mood/neuropsychiatric disorders (63). In line with this, the administration of either antidepressant drugs or the naturally occurring autophagy inducer resveratrol alleviates depressive-like behavior in mice models of CUMS or post-partum depression by increasing BDNF and autophagyassociated proteins (136,138). This goes along with reduced HPA axis hyperactivity, CRF and pro-inflammatory cytokines levels (136,138).…”